Devices and methods for low pressure tumor embolization

ABSTRACT

A method of transarterial embolization agent delivery at a low pressure is provided. The method comprises advancing a delivery device with an occlusion structure in a retracted non-occlusive configuration through a supply artery to a vascular position in the supply artery that is in the vicinity of a target anatomical structure, the target structure having terminal capillary beds, expanding the occlusion structure from the retracted non-occlusive configuration to an expanded occlusive configuration, lowering a mean arterial pressure in a vascular space distal to the expanded occlusion structure, redirecting fluid flow from the collateral vessels toward the lowered pressure vascular space and into the target anatomical structure, injecting an embolization agent through the delivery device and into the lowered pressure vascular space, and delivering the embolization agent from the lowered pressure vascular space into the target anatomical structure. Other catheter assemblies and methods of use are also disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.14/954,699 filed Nov. 30, 2015, which is a divisional of U.S.application Ser. No. 14/273,445 filed May 8, 2014, now U.S. Pat. No.9,205,226, which claims the benefit of U.S. Provisional Application No.61/821,058 filed May 8, 2013, U.S. Provisional Application No.61/915,425 filed Dec. 12, 2013, and U.S. Provisional Application No.61/917,131 filed Dec. 17, 2013, each of which is herein incorporated byreference in its entirety.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

GOVERNMENT RIGHTS

This invention was made with Government support under Grant No. 1417279awarded by the National Science Foundation. The Government has certainrights in this invention.

FIELD

This application relates generally to medical methods and devices. Morespecifically, the present application discloses various embodiments ofocclusion devices adapted to a catheter, and methods for their use indelivering fluids, embolic materials and other therapeutic agents tosites within the body.

BACKGROUND

There are over one million cases of cancer diagnosed each year in theUnited States and numerous approaches of therapy including systemicchemotherapy, radiation and surgical resection. Given that systemicchemotherapy and radiation interact with healthy tissue, complicationsand toxicity often result. Targeted drugs are now being used and producea lower rate of complications. Ablative approaches, including microwave,radiofrequency and cryogenic therapies have been used; however, thesemethods are often not selective and tissues and organs surrounding orbelow the tumor can be affected.

According to the National Institute of Health, 30,640 people werediagnosed with primary liver cancer (hepatocellular carcinoma, HCC) and142,820 people were diagnosed with colorectal cancer in the U.S. in2013. Seventy-five percent of these will metastasize to the liver. Liverresection and transplant are the only curative means; however, onlysmall numbers of patients are eligible. Systemic chemotherapy forprimary and metastatic tumors in the liver is ineffective, having aresponse rate of about 20% and a survival benefit of 10.7 months vs. 7.9months over symptomatic care.

Catheters are commonly used in medicine for delivery of fluids,therapeutics, and implants, and in sampling tissues and bodily fluids.Catheters can be constructed with balloons or other tools to dilatetissue, block fluid flow or isolate segments of the anatomy, such as intreatment of the cancers described above.

Transvascular fluid delivery via arteries or veins is typically used todistribute materials throughout the body and without consideration of aspecific target tissue or organ. One notable exception to this is theuse of compounds, such as anti-cancer agents that are conjugated toantibodies that target a specific binding site. Anti-tumor agents canalso be fashioned to bind to specific cell receptors and block cellularfunctions of cancer cells. In this way, cytotoxic therapies seek outcancer cells and avoid healthy tissues, reducing systemic toxicity.

However, most drugs are not conjugated or otherwise contrived to seekout a target and drugs that are injected are distributed throughout thebody, even though the beneficial effect is limited to one or severaltarget sites. Delivery of drug to non-target sites can causecomplications and result in considerable morbidity.

Trans-Arterial Embolization therapy is the transvascular injection ofdrug and/or embolic agents directly into the tumor vasculature using amicrocatheter. Embolization therapy causes a shutdown of blood flow and,when drug or radioactivity is present, simultaneous release of highconcentrations of drug or radioactivity. The technique is also noted forits very low level of toxicity.

In the early 1980's, transarterial chemoembolization (TACE) began to beused as a selective cancer therapy. In this method, chemotherapeutic andembolic agents are injected directly into the vasculature of the tumor,a technique that is most common for the treatment of hepatocellularcarcinoma. More recently, transarterial radioembolization (TARE) hasbeen used clinically. In this method, radioactive embolic particles,typically yttrium-90 (y90), are injected rather than chemotherapeuticagents. Although the liver is a common target for TACE and TARE, otherorgans, including, but not limited to, the pancreas, lung, kidney,prostate, stomach, colon and head and neck have been treated using thesemethods. Chemoembolization was established as a standard of care forintermediate stage hepatocellular carcinoma in 2006.

Numerous studies have demonstrated transarterial embolization to beeffective on a number of primary cancers and to have better performancethan chemotherapy for both HCC and metastatic colorectal cancers in theliver; however, studies show inconsistent outcomes with reported tumorresponses from 15% to 85%. Although anatomical and individualdifferences are clearly of significance in between-patient variation,clinical studies, each of which include numerous patients, show verydifferent outcomes, indicating that the procedure is not reproducibleand that there is little procedural optimization or standardization.

The above procedures are accomplished by inserting a small catheter intothe femoral artery at the groin or radial artery of the forearm andnavigating it into the liver vasculature, typically the hepatic artery,then into the right or left lobe of the liver or more selectively intoparticular segments of the liver or super-selectively directly into oradjacent to the tumor. Typically, the tip of the microcatheter ispositioned in a supply artery that is proximal to the tumor feederartery and collateral arteries that branch from the supply artery andflow toward healthy tissues. In this instance, blood flows over thecatheter tip and into the tumor and collateral arteries that feedhealthy tissues. Injection of embolic agents will follow blood flow anddeposit into both the tumor and healthy tissues (non-targetembolization). Presently, standard microcatheters, typically at or about3 Fr, are used to inject antitumor agents into the target vasculature.These standard microcatheters rely on normal blood flow as the means bywhich the embolic agent moves into the tumor and systolic and/or meanarterial pressure as the packing force. However, as the tumor begins tobecome embolized, it cannot accept the normal rate of blood flow andintra-tumor pressure rises to a point where the tumor can no longeraccept the blood flow and the blood begins to reflux into the tumorfeeder and supply artery. At this point tumor embolization can no longerproceed since embolization agents are refluxing out of the tumor alongwith the blood, even though the tumor is only partially filled withembolic agents. Under these conditions, further injection of embolicagents results in high pressures in the supply artery and a concomitantincrease in non-target flow of embolic agents to healthy tissues andreflux backwards over the catheter. This situation also results in lossof an unknown amount of drug which, at least in part, explains theirreproducibility of the technique.

The endpoint of the above procedures is determined by physicians' visualobservation of contrast flow and therefore the amount of dose deliveredis highly variable. Reflux, non-target embolization in antegrade andretrograde directions, distribution of embolic agents, packing andquantity of dose delivered are variables that can be highly dependent onthe rate and pressure of injection, the selection of the type ofendpoint, the patient's systolic and/or mean arterial pressure, anatomyand the operator. As such, clinical trials using TACE to treathepatocellular carcinoma have demonstrated wide variations in tumorresponse. The most significant clinical problems that occur with thecurrent means of delivery and methods of embolization therapy includeinconsistent efficacy and complications from non-target embolization.

Using standard straight-tip catheters, non-target embolization in theretrograde and antegrade directions can be caused when the pressure ofinjection exceeds the mean arterial blood pressure whereby embolicagents flow into healthy tissues causing complications.

Antegrade

When therapeutic agents are delivered into the vasculature of a targetstructure using the normal antegrade blood flow to carry the therapy tothe target, antegrade non-target flow is unavoidable and injection rateof therapeutic agents must be carefully controlled in relation to thethen present flow volume and pressure of blood to avoid an increasedamount of antegrade non-target flow and reflux of drug backward over thecatheter and into healthy tissues. In particular, when injecting embolicagents into the vasculature of a tumor, pressure distal to the cathetertip continues to increase as embolization progresses, causing aresistance that prevents embolic agents from filling the targetvasculature and the possibility of reflux and non-target flow andembolization. It would be desirable to eliminate this antegradenon-target flow and reflux, and the inconsistent dosages that aredelivered to targets with current state of the art procedures. It wouldbe further desirable to eliminate the low levels of particledistribution and density throughout the target vasculature. It would bestill further desirable to replace current delivery devices that are notalways capable of fully isolating the target vasculature and often donot allow the operator to control pressure, flow rate and otherparameters associated with therapeutic delivery.

The present state-of-the-art embolization therapy using standardstraight-tip microcathetes for tumors in the liver relies on high volumeforward flow from the hepatic artery (supply artery) to deliverembolization agents into the tumor. However; as tumor embolizationproceeds, larger arterioles and capillaries are filled first, thissubstantially stopping flow in these vessels which causes: (1) highintra-tumor vascular pressure, (2) high pressure in arteries feeding thetumor, (3) high pressure in the supply artery, (4) reflux over thedelivery catheter, (4) increased antegrade non-target flow intohepatoenteric arteries and (5) poor filling and distribution of embolicagents in the tumor. This situation results in an uncontrollable andirreproducible number of particles entering the tumor and highprocedural variability.

Problems with the current method of embolization therapy that causeinconsistent outcomes include: high flow rates into the tumor, variableprocedural endpoints, unknown quantity of dose delivered, reflux ofembolization agents, antegrade non-target flow of embolization particlesinto branch arteries, rising intra-tumor arterial pressures during theinitial stages of embolization, catheter movement during injection,catheter tip position and the catheter not being centered in the bloodvessel. The current delivery catheters are unable to control many of theabove mentioned variables, producing inconsistent outcomes and makingany standardization of the current procedures difficult or impossible toachieve.

The following patents and published patent applications provide someexamples of the current state of this art. U.S. Pat. No. 5,647,198describes a catheter with a pair of spaced apart balloons that define anintra-balloon space. A lumen passes through the catheter and exitswithin the intra-balloon space allowing injection of drugs, emulsions,fluids and fluid/solid mixtures. A perfusion lumen or bypass extendsfrom a location proximal to the proximal balloon and to the distal tipto allow shunting of blood past the inflated balloons. U.S. Pat. No.5,674,198 describes a two balloon catheter that is designed for treatinga solid tumor. The balloons are positioned to isolate the blood flowinto the tumor and allow injection of a vaso-occlusive collagen materialto block the tumor blood supply. Clifton et al. (1963) Cancer 16:444-452describes a two balloon catheter for the treatment of lung carcinoma.The four lumen catheter includes a lumen for independent injection inthe space between the balloons. Rousselot et al. (1965) JAMA 191:707-710describes a balloon catheter device for delivering anticancer drugs intothe Liver. See also U.S. Pat. No. 6,780,181; U.S. Pat. No. 6,835,189;U.S. Pat. No. 7,144,407; U.S. Pat. No. 7,412,285; U.S. Pat. No.7,481,800; U.S. Pat. No. 7,645,259; U.S. Pat. No. 7,742,811; U.S. App.No. 2001/008451; U.S. App. No. 2001/0041862; U.S. App. No. 2003/008726;U.S. App. No. 2003/0114878; U.S. App. No. 2005/0267407; U.S. App. No.2007/0137651; U.S. App. No. 2008/0208118; U.S. App. No. 2009/0182227 andU.S. App. No. 2010/0114021.

What is needed, and not provided by the prior art, are delivery devicesand methods that enable exclusive delivery of drug to a target area ofthe anatomy and elimination or reduction of the flow of drug outside ofthe target area.

SUMMARY OF THE DISCLOSURE

According to aspects of the present disclosure, devices and methods areprovided for full or partial occlusion that are designed to be adaptedto a catheter for delivery of therapeutic agents to a target site withinthe body. Such delivery devices may be intended for any medical purpose,but the embodiments described herein are focused on devices intended forperforming transarterial delivery of therapeutic agents to a target sitewithin the body. The entry point for the delivery catheter can be anyarterial access point, typically the femoral artery located at the groinor the radial artery in the forearm. The target can be any structure;however, of particular interest are tumors, primary or metastatic, ofany organ or tissue that is accessible by a microcatheter through thearterial system. Cancers of particular interest include, but are notlimited to, primary and metastatic cancers in the liver, pancreas,colon, rectum, kidney, stomach, lung, bladder, head and neck, prostateand uterus. Procedures that can benefit from the access and deliverymethods and devices of the present disclosure include, but are notlimited to, transarterial chemoembolization using drug eluting beads(DEB TACE), transarterial chemoembolization using Lipiodol (LipiodolTACE), transarterial radioembolization (TARE) and transarterialembolization (TAE). Other procedures which can benefit from methods anddevices of the present disclosure include direct delivery ofchemotherapy or targeted drugs to the site of the cancer, the generaldelivery of drugs, venous or arterial embolization or other substancesto specific regions of the body and drainage or aspiration of fluid ortissue. Of particular interest are embolization of the prostate, as atherapy for benign prostatic hyperplasia (BPH), and embolization of theuterus, as a therapy for uterine fibroids.

The occlusion device of the present disclosure causes an immediatepressure drop in the vascular area distal to the occlusion, creating alow pressure zone in the distal artery and surrounding tissue. Sincefluid will flow from high pressure to low pressure, blood flow willredistribute in favor of the low pressure zone. When a tumor or otherstructure with terminal capillary beds is within, or in the vicinity of,the low pressure zone, the blood will flow toward the terminalcapillaries since they empty in to veins that have very low pressure. Inthis instance, the anatomical structure with terminal capillaries actsas a sump that accepts blood flow from surrounding area. By way ofexample, embolization of tumors in the right lobe of the liver areaccessed by a catheter advanced through the right hepatic artery (RHA)and to the vicinity of the tumor. Typically, the catheter tip does notenter the tumor vasculature and remains proximal to the tumor and withinthe right hepatic artery or branch thereof. In this example, the arteryfeeding the tumor is typically a branch of the RHA. However, there otherdistal hepatoenteric arteries that branch from the RHA and flow awayfrom the RHA and to the liver and gastrointestinal tract. In thisinstance, when using a standard straight catheter, injection of embolicagents from the distal tip of the catheter results in flow of embolicagents into both the tumor and collateral arteries causing antegradenon-target embolization of the liver and gastrointestinal tract, asituation that causes toxicity and complications. The device and methodof the present disclosure causes a flow redistribution wherebycollateral arteries reverse flow in favor of the tumor, minimizingnon-target flow and increasing the number of embolic particles thatenter the tumor.

In some embodiments, the methods and devices disclosed herein include aballoon or other structure that can be expanded or activated to create afull occlusion of the target blood vessel with a concomitant reductionin pressure and flow rate in the anatomical zone distal to the fullocclusion that can: (1) eliminate reflux, (2) reduce or eliminateantegrade non-target flow, (3) reduce or eliminate non-targetembolization, (4) reduce flow rate and volume moving into the tumor, (5)slow the increase of intra-tumor pressure, (6) slow the onset of bloodreflux from the tumor, (7) increase the time that embolic agents canenter the tumor, (8) increase the amount and distribution of embolicagents that are deposited in the tumor, (9) isolate the vascular areadistal to the occlusion from the general circulation, (10) create a lowpressure zone in the vicinity of the tumor and (11) cause a generalinflow of blood toward the low pressure area created by the occlusion.

In other embodiments, the microcatheter methods and devices disclosedherein, include a balloon or other structure that can be expanded oractivated to create a partial occlusion of the target blood vessel suchas by creating channels from the proximal end of the occlusion structureto the distal end of the occlusion structure. When in the expandedconfiguration there is a concomitant reduction in pressure and flow ratein the anatomical zone distal to the occlusion. The device of thisembodiment can: (1) provide a distal directed bypass (forward flow) ofblood, (2) eliminate reflux, (2) reduce or eliminate antegradenon-target flow, (4) reduce or eliminate non-target embolization, (5)reduce flow rate and volume moving into the tumor, (6) slow the increaseof intra-tumor pressure, (7) slow the onset of blood reflux from thetumor, (8) increase the time that embolic agents can enter the tumor,(9) increase the amount and distribution of embolic agents that aredeposited in the tumor, (10) isolate the vascular area distal to theocclusion from the general circulation, (11) create a low pressure zonein the vicinity of the tumor and (12) cause a general inflow of bloodtoward the low pressure area created by the occlusion.

In some embodiments, a catheter assembly may be provided with a catheterbody and an inflatable balloon. The catheter body has a proximal end, adistal end and a balloon inflation lumen. The inflatable balloon isattachable to the distal end of the catheter body. The balloon has aninner surface that at least partially defines an interior volume. Theballoon is configured such that the interior volume can be in fluidcommunication with the inflation lumen of the catheter body to inflatethe balloon. The balloon also has a proximal surface and a distalsurface. The balloon is provided with a channel that extends through theballoon as in partial occlusion or the balloon is without channels as infull occlusion. If present, the channel may be configured to providefluid communication between the proximal surface of the balloon and thedistal surface of the balloon.

In some embodiments, a device for delivering a therapeutic agent to atarget site within a body is provided. The device comprises a catheterbody having a proximal end, a distal end, a first axial lumen and asecond axial lumen. The first axial lumen extends from the proximal endof the catheter body to the distal end of the catheter body and providesfluid communication therebetween. The second axial lumen extends fromthe proximal end of the catheter body to a more distal location on thecatheter body. The device further comprises a balloon radially disposednear the distal end of the catheter body. The balloon has a proximalballoon surface, a distal balloon surface, a radially constrainedconfiguration and a radially expanded configuration. The balloon is influid communication with the second axial lumen and is a full occlusionballoon or has at least one channel, said channel extending from theproximal balloon surface to the distal balloon surface, therebyproviding fluid communication therebetween.

In some embodiments, a method of embolization of a tumor is provided.The method comprises advancing a device including a catheter body and apartial occlusion structure to a supply artery in the vicinity of atarget tumor site within the body, and allowing an antegrade blood flowpast the partial occlusion structure. The allowed antegrade blood flowis less than a blood flow that would normally be present if the partialocclusion structure were not in place. The partial occlusion produces apressure drop in the anatomic zone distal to the occlusion, flowredistribution of collateral arteries and capillaries associated withthe supply artery and flow being directed into and through the tumorinto the venous system. The method further comprises injecting anembolic substance from the device to allow the antegrade blood flow tocarry the embolic substance into a vasculature of the tumor andwithdrawing the device from the body.

By isolating the distal arterial space that is adjacent to the tumorfrom the arterial blood supply, the device of the present disclosureenables pressure measurement to be used to signal a procedural endpointat a predetermined pressure or pressures. By way of example, theendpoint of the procedure can occur at a point when systolic pressure(120 mmHg) is first reached or at a point when systolic pressure and/ormean arterial pressure is stabilized, however any pressure, pressureprofile or algorithm can be used to determine an endpoint of theprocedure. Such a measurable endpoint can contribute to standardizationof the procedure and improved efficacy.

The occlusion structure of the device of the present disclosure may beheld within a pocket within the catheter such that the outer diameter ofthe radially constrained occlusion structure is approximately equal toor less than the outer diameter of the catheter as described inco-pending U.S. patent application Ser. No. 15/044,864 and issued U.S.Pat. No. 9,205,226. The pocket can be a longitudinal space in thecatheter and can be formed as a reduction in the catheter diameter of adefined length and a depth equal to or greater than the thickness of theocclusion structure in a radially constrained configuration.Alternately, a pocket can be formed using an extension projectingdistally beyond the catheter body, the distal extension having adiameter smaller than the catheter body. In this instance, the distalend of the catheter pocket is defined by the proximal end of anose-piece. In some embodiments, the nose-piece has a diameter equal toor less than the diameter of the catheter body and is positioned overthe distal extension at a defined distance from the distal end of thecatheter body.

The occlusion structure of devices of the present disclosure can beadvanced in a radially constrained configuration, to at least theproximity of a target within the body and then placed in its radiallyexpanded configuration. Alternately, the device can be pre-formed in afully expanded configuration, adapted to the distal end of a catheterand delivered to the target site.

Antegrade

According to aspects of the present disclosure, methods of transarterialembolization agent delivery at a low pressure are provided. In someembodiments, the method comprises advancing a delivery device with anocclusion structure in a retracted non-occlusive configuration, througha supply artery having a plurality of collateral vessels that branchtherefrom and being in fluid communication with a target anatomicalstructure, to a vascular position in the supply artery that is in thevicinity of the target anatomical structure. The target structure hasterminal capillary beds. The method further comprises expanding theocclusion structure from the retracted non-occlusive configuration to anexpanded occlusive configuration, lowering a mean arterial pressure in avascular space distal to the expanded occlusion structure, andredirecting fluid flow from the collateral vessels toward the loweredpressure vascular space and into the target anatomical structure. Themethod further comprises injecting an embolization agent through thedelivery device and into the lowered pressure vascular space, anddelivering the embolization agent from the lowered pressure vascularspace into the target anatomical structure.

In some embodiments, the mean arterial pressure in the lowered pressurevascular space is lowered during the lowering step to between 10% and60% of a normal mean arterial pressure. The lowering step may comprisemeasuring a pressure in the vascular space after expanding the occlusionstructure. The lowering step may further comprise ensuring the measuredpressure is within a predetermined range before proceeding with theinjecting step. In some embodiments, the lowering step comprises waitinga predetermined period of time before proceeding with the injecting stepto ensure that a sufficient pressure drop has occurred.

In some embodiments, the mean arterial pressure of the lowered pressurevascular space is kept below an un-occluded starting pressure by atleast 10% of the difference between the un-occluded starting pressureand a stabilized occluded pressure during the injecting step. In someembodiments, the mean arterial pressure of the lowered pressure vascularspace is kept below an un-occluded starting pressure by at least 30% ofthe difference between the un-occluded starting pressure and astabilized occluded pressure during the injecting step.

In some embodiments the fluid is predominantly blood or interstitialfluid. The embolization agent may be injected with a flow rate in therange of 0.25 to 6 ml/minute. The delivery device may comprise acatheter, a needle, or a cannula. In some embodiments, the occlusionstructure allows a fluid flow of 5 to 25% of normal to bypass theocclusion structure after it has been expanded into the occlusiveconfiguration. In some embodiments, the occlusion structure creates asubstantially full occlusion having less than 2% bypass blood flow.

In some embodiments, the occlusion structure comprises a balloon. Theballoon may be provided with a generally v-shaped channel extendingalong a least a portion of its length, thereby providing a fluid bypasschannel when the balloon is inflated. The balloon may be provided with aspiral channel extending from a proximal end of the balloon to a distalend, thereby providing a fluid bypass channel when the balloon isinflated. In some embodiments, the delivery device is provided with apressure transducer located distal to the occlusion structure andconfigured to sense fluid pressure when located in the supply artery.

In some embodiments, the target anatomical structure is a tumor, aprostate, or a uterus.

While aspects of the present disclosure will be described withparticular reference to delivery of chemotherapeutic agents,radiotherapeutic agents, embolic agents or combinations thereof into thevasculature that supplies blood to a tumor, the same principles apply tothe delivery or aspiration of a variety of materials into or from otherlocations, and through other luminal structures in the body.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the disclosure are set forth with particularity inthe claims that follow. A better understanding of the features andadvantages of the present disclosure will be obtained by reference tothe following detailed description that sets forth illustrativeembodiments, in which the principles of the disclosure are utilized, andthe accompanying drawings of which:

FIGS. 1A, 1B and 1C illustrate embodiments of the disclosure herein;

FIG. 2 illustrates a distal cross sectional view of a bidirectionalembodiment;

FIG. 3 illustrates a unidirectional embodiment;

FIG. 4 illustrates a unidirectional embodiment with balloon inflationand guidewire/injection lumens;

FIG. 5 illustrates an embodiment of the present disclosure including adistal tip and adapter;

FIG. 6 illustrates an embodiment of the present disclosure with abidirectional channel within the catheter;

FIG. 7 illustrates an embodiment of the present disclosure with aunidirectional channel;

FIG. 8 illustrates a device of the present disclosure with a distal tip;

FIG. 9A shows a linear cross section through the catheter and balloon;

FIG. 9B shows a linear cross section through the catheter and balloonand two circular bidirectional channels;

FIG. 9C shows a linear cross section through the catheter and balloonand three circular bidirectional channels;

FIG. 9D shows a linear cross section through the catheter and balloonand two circular unidirectional bypass channels with individual valveson each channel;

FIG. 9E shows a linear cross section through the catheter and balloonand three circular unidirectional bypass channels with individual valveson each channel;

FIG. 9F shows a linear cross section through the catheter and balloonand two circular unidirectional channels with a one-piece valve coveringboth channels;

FIG. 9G shows a linear cross section through the catheter and balloonand two circular unidirectional channels with a one-piece valve coveringthree channels;

FIG. 9H shows a linear cross section through the catheter and balloonand four bidirectional bypass channels formed from pleats in theballoon;

FIG. 9I shows a linear cross section through the catheter and balloonand four unidirectional bypass channels formed from pleats in theballoon and a one-piece valve covering all 4 channels;

FIG. 9J shows a linear cross section through the catheter and balloonand four bidirectional channels which radiate outward from the catheter;

FIG. 9K shows a linear cross section through the catheter and balloonand four unidirectional channels which radiate outward from the catheterand a one-piece valve covering all four valves;

FIG. 9L shows a linear cross section through the catheter and balloonand four unidirectional channels which radiate outward from the catheteroutward and a single cross shaped valve covering all four channels;

FIG. 10 shows a tumor and associated vasculature;

FIG. 11 shows an expanded view of a tumor and its vasculature includingblood flow direction;

FIG. 12 illustrates a standard micro-catheter over a guidewire insidethe tumor vasculature with injection;

FIG. 13 illustrates a catheter of the present disclosure over aguidewire and inside a main artery

FIG. 14 illustrates a catheter of the present disclosure over aguidewire and inside the branch artery;

FIG. 15 illustrates a catheter of the present disclosure with inflatedballoon and closed valves;

FIG. 16 illustrates a catheter of the present disclosure with inflatedballoon and open valves;

FIG. 17 illustrates a catheter of the present disclosure with inflatedballoons, open valves and initiation of fluid injection;

FIG. 18 illustrates a catheter of the present disclosure duringinjection with inflated balloons and valves closed;

FIG. 19 illustrates a catheter of the present disclosure at a period oftime following the completion of injection with inflated balloon andopen valves;

FIG. 20 shows the deflation of the balloon;

FIG. 21 shows the withdrawal of the catheter into a main artery;

FIG. 22 shows an embodiment of the present disclosure with a channelwithin the catheter and closed valve;

FIG. 23 shows an embodiment of the present disclosure with a channelwithin the catheter and open valve.

FIG. 24A illustrates a standard microcatheter;

FIGS. 24B, 24C, 24D and 24E illustrate a cross sectional view of asequential construction of an embodiment of the present disclosure;

FIGS. 25A and 25B illustrate a cross sectional view of the distalportion of one embodiment of the device according to the presentdisclosure;

FIGS. 26A and 26B illustrate a view of an embodiment including anocclusion balloon concealed within pocket formed between proximal anddistal surfaces;

FIGS. 27A and 27B illustrate a distal catheter with and occlusionballoon unexpanded and expanded;

FIGS. 28A, 28B, 28C, and 28D illustrate an embodiment of the presentdisclosure including a two layer catheter;

FIG. 29 gives examples of balloons used in various embodiments of thepresent disclosure;

FIG. 30 shows a front view of a balloon with one-way bypass channels andvalves;

FIG. 31 shows a cross section through the balloon of FIG. 30;

FIGS. 32A, 32B, 32C, 32D, 32E and 32F illustrate a cross sectional viewof a sequential construction of an embodiment of the present disclosureincluding a balloon pocket and integral nose cone;

FIGS. 33A, 33B, 33C, 33D and 33E illustrate a cross sectional view of asequential construction of an embodiment of the present disclosureincluding a balloon pocket and separate nose cone;

FIG. 34 illustrates an embodiment of the present disclosure with twoballoons;

FIG. 35 illustrates an embodiment of the present disclosure including aballoon with valves;

FIG. 36 illustrates an embodiment of the present disclosure withpressure sensors;

FIGS. 37A, 37B, 37C and 37D illustrate an embodiment of the presentdisclosure with a balloon or balloons placed on the circumference of thecatheter;

FIGS. 38A and 38B illustrate a tumor with vascular anatomy andembolization using a standard straight nose catheter;

FIGS. 39A and 39B illustrate a tumor with vascular anatomy andembolization using a balloon including channels and valves;

FIGS. 40A, 40B, 40C and 40D illustrate a tumor with vascular anatomy andembolization using an occlusion balloon;

FIGS. 41A, 41B, 41C, 41D, 41E, 41F and 41G illustrate constructions ofembodiments of the present disclosure;

FIGS. 42A, 42B, 42C and 42D illustrate a two layer occlusion structurewith unidirectional flow;

FIG. 43 illustrates a prototype of the occlusion structure of FIG. 42;

FIGS. 44A and 44B illustrate an embodiment of the present disclosureincluding a catheter with a pocket;

FIGS. 45A and 45B illustrate embodiments of the present disclosure forcomplete occlusion;

FIGS. 46A and 46B illustrate an embodiment with bidirectional andunidirectional channels;

FIGS. 47A and 47B illustrate valve constructions of an embodiment of aunidirectional occlusion structure of the present disclosure;

FIGS. 48A and 48B show a prototype micro-valve;

FIGS. 49A and 49B show an alternate embodiment of an occlusionstructure;

FIGS. 50A, 50B and 50C illustrate a method of operation of oneembodiment of a unidirectional occlusion structure of the presentdisclosure;

FIGS. 51A, 51B, 51C, 51D, 51E and 51F illustrate a method for deliveryof embolic particles using a device of the present disclosure;

FIG. 52 illustrates a partial occlusion balloon with channel and valve;

FIG. 53 illustrates a side view of constrained occlusion balloon incatheter pocket;

FIGS. 54A, 54B and 54C illustrate a distal end construction includingpocket, constrained balloon and expanded partial occlusion balloon withchannels and valves in closed position;

FIGS. 55A, 55B and 55C illustrate a serial construction of a full lengthcatheter device;

FIG. 56 illustrates liver vasculature and associated tumor vasculature;

FIGS. 57A, 57B, 57C, 57D, 57E, 57F, 57G and 57H illustrate a tumorembolization method for a standard catheter;

FIGS. 58A, 58B, 58C, 58D and 58E illustrate a tumor embolization methodfor the catheter of the present disclosure;

FIGS. 59A, 59B, 59C and 59D illustrate fabrication steps of the distalend of an occlusion catheter according to aspects of the presentdisclosure;

FIG. 60 illustrates the completed distal end of the occlusion catheterof FIGS. 59A-59D being introduced into small branches of a vascularsystem;

FIG. 61A shows an entire occlusion catheter constructed according toprinciples of the present disclosure;

FIG. 61B shows details of construction features on the distal end of theocclusion catheter of FIG. 61A;

FIG. 62 shows a representative arterial system located adjacent totarget tissue, before occlusion;

FIG. 63 shows the representative arterial system of FIG. 62 after atemporary occlusion is introduced;

FIG. 64 shows target tissue and immediately adjacent arteries andcapillaries, before occlusion;

FIG. 65 shows the target tissue and immediately adjacent arteries andcapillaries of FIG. 64 after a temporary occlusion is introduced intothe target artery;

FIG. 66 is a chart showing pressure vs. time for an exemplary lowpressure embolization method according to aspects of the presentdisclosure compared with a standard embolization procedure;

FIG. 67 is an axial cross-section showing an alternative catheterballoon design;

FIG. 68 shows an embodiment of a catheter balloon having spiralchannels, shown in a deflated configuration;

FIG. 69 shows the balloon of FIG. 68 in an inflated configuration;

FIG. 70 shows an in-vivo tumor flow model developed in Phase 1B ofanimal testing, in particular illustrating a normal blood flow pattern;

FIG. 71 shows the in-vivo tumor flow model of FIG. 70, with a standardembolization catheter maintaining a normal blood flow pattern;

FIG. 72 shows the in-vivo tumor flow model of FIG. 70, with an inventiveembolization catheter creating blood flow redirection; and

FIG. 73 is a table summarizing bead collection results of the animaltesting.

DETAILED DESCRIPTION

The device of the present disclosure allows improved distribution ofanti-cancer agents into target tumor vasculature by reducing arterialflow and pressure during drug and/or embolic agent injection. Thepresent device reduces toxicity and complications by eliminating refluxof embolic materials and/or anti-cancer agents into proximal arterialbranches and reduces or eliminates antegrade bypass of embolic materialsand/or anticancer agents into distal arterial branches. Further, thepresent disclosure enables pressure measurement as a means to aquantitative endpoint of the procedure. Such a device can improveefficacy and reproducibility of the technique and reduce complications.

Referring to FIG. 1A, a longitudinal cross section of device 2 of thepresent disclosure is shown with catheter body 4, distal tip 6, balloon8 (unexpanded configuration), balloon inflation tube 10, guidewire andinjection tube 12 and fittings 14. Catheter body 4 can have a length of10 cm to 400 cm, typically 60 cm to 250 cm and a diameter of 0.25 mm to5 mm, typically 0.5 mm to 1.5 mm. Device 2 may or may not include adistal tip 6, the distal tip having a length of 1 mm to 50 mm, moretypically from 5 mm to 30 mm. The balloon inflation tube 10, positionedat the proximal end of catheter body 4, is connected to, and in fluidcommunication with a balloon inflation lumen that runs longitudinallythrough the length of catheter body 4 and terminates at, and is in fluidcommunication with balloon 8. The guidewire and injection tube 12,positioned at the proximal end of catheter body 4, is connected to, andin fluid communication with a lumen that runs longitudinally through thelength of catheter body 4 and terminates at the distal end or distal tipof catheter body 4, thereby allowing a guidewire to enter throughfitting 14 and exit through the distal end of device 2 through catheterbody 4. Fittings 14 are connected to each of balloon inflation tube 10and guidewire and injection tube 12 and can connect to a syringe,inflation device or any other device or means to inject air, gas, fluid,suspensions, emulsions, contrast, therapeutic agents, embolic agents orany other material capable of being injected through balloon tube 10 orguidewire tube 12 and longitudinal lumens that run to the balloon ordistal end of device 2.

Referring to FIG. 1B, a longitudinal cross section of a first embodimentof the present disclosure is shown, with device 2, balloon 8 (in theexpanded configuration) having valve 16 in the open position and valve18, in the closed position. In this embodiment flow channels 20 and 22are constructed through balloon 8. Valves 16 and 18 allow fluid to flowin only one direction. Balloon 8 has a proximal side 9 and a distal side11. By way of example, if fluid pressure is higher on the proximal sideof balloon 8 and lower on the distal side of balloon 8, both valves 16 &18 will open in response to the pressure difference and allow fluid toflow distally through the valves. If the pressure is higher on thedistal side of balloon 8, valves 16 and 18 will close and prevent fluidfrom flowing proximally. Alternately, the valves can be position orconstructed so that fluid can pass proximally and be prevented fromflowing in the distal direction. Valves 16 and 18 are shown as a simple“flap” type valve, however, they can be any type of valve, such as adiaphragm that open and close in response to a pressure differential.Balloon 8 is shown with two channels and two valves; however there canbe 1, 2, 3 or more channels and/or valves. Device 2 of this embodimentmay include channels and may or may not include valves. If valves arenot included, a bidirectional flow will result.

Referring to FIG. 1C, a longitudinal cross section of another embodimentof the present disclosure is shown with device 24 and channel 26 runningthrough and within catheter body 28. Balloon 30 has a proximal side 13and a distal side 15. Channel 26 extends from the proximal side ofballoon 30 to the distal side of balloon 30. A valve 32 is illustratedover channel 26 on the distal side of balloon 30, however, if desiredthe valve can be positioned on the proximal side of channel 26 andballoon 30. The function and operation of valve 32 of this embodiment ofthe present disclosure is identical to that presented in FIG. 1A andFIG. 1B. As in this embodiment, if valve 32 is not included, abidirectional flow will result.

FIG. 2 illustrates an exemplary embodiment of a longitudinal crosssection of the distal end of device 2 with catheter body 4, ballooninflation lumen 34, balloon 8, and channel 38. Balloon inflation lumen34 extends from the proximal end of catheter body 4 and exits at balloon8. In this case, a valve in balloon 8 is not included and abidirectional flow will result. The optimal balloon inflation lumendiameter is 0.1 mm to 0.5 mm; however this lumen can be in the range of0.25 mm to 1 mm.

FIG. 3 illustrates an example of a longitudinal cross section of thedistal end of device 2 with catheter body 4, balloon inflation lumen 34,balloon 8, channel 38 and valve 16. Valve 16 is shown over the distalopening of channel 38 in the closed position, however if pressure isapplied to the proximal valve surface through channel 38, the valve willallow fluid to pass distally. The valve 16 will prevent proximal flow.The valve can be positioned at the proximal or distal opening oranywhere within the cannel. Location and configuration of the valve willdetermine flow direction.

Referring to FIG. 4, a longitudinal cross section of the distal end ofdevice 2 is shown with catheter body 4, balloon inflation lumen 34,balloon 8, channel 38 and guidewire/injection lumen 40.Guidewire/injection lumen 40 extends from the proximal end of catheterbody 4 and exits at the distal end of catheter body 4 or distal tip 6.The optimal guidewire/injection lumen diameter is 0.1 to 1.0 mm;however, this lumen can be in the range form 0.025 mm to 2 mm.

Referring to FIG. 5, an example of a longitudinal cross section of thedistal end of device 2 is shown with catheter body 4, balloon inflationlumen 34, balloon 8, channel 38, guidewire/injection lumen 40, adapter42, balloon pocket 44 and distal tip 6. Distal tip 6 has an optimaldiameter of 0.3 mm to 1.3 mm; however, distal tip 6 can range from 0.1mm to 4 mm. Adapter 42 is adapted to create a smooth transition from thedistal tip 6 to the catheter body 4. By way of example, if the distaltip 6 is 1 mm in diameter and the catheter body 4 is 2 mm in diameter,the adapter will taper from a diameter of 1 mm at its distal most pointto 2 mm at its proximal most point to create a smooth transition fromthe smaller diameter distal tip to the larger diameter catheter body. Asshown in FIG. 5, adapter 42 is positioned on the distal tip 6 at alocation that is distal to distal end of catheter body 4, such that aballoon pocket 44 is formed between the distal end of catheter body 4and the proximal end of adapter 42. Balloon pocket 44 holds unexpandedballoon 8 such that its unexpanded profile is minimized. Optimallyballoon 8 would conform to an outer diameter that is equal to thediameter of the catheter body 4. By way of example, if the distal tipdiameter is 1 mm and the catheter body is 2 mm, a balloon pocket isformed that is 0.5 mm deep. If balloon 8 is no more than 0.5 mm thickwhen unexpanded, it will lie equal to or below the surface of catheterbody 4. This allows facilitation of the movement of the caterer withinthe artery or vein.

Referring to FIG. 6, a longitudinal cross section of the distal end ofdevice 24 is shown with catheter body 28, balloon inflation lumen 50,guidewire/injection lumen 52, balloon 30, and channel 26 with proximalport 54 and distal port 56. Channel 26 passes through and withincatheter body 28 and extends from the proximal side of balloon 30 to thedistal side of balloon 30. Port 54, at the proximal end of channel 26 isin fluid communication with the outside of the catheter body that isproximal to balloon 30 and port 56, at the distal end of channel 26, isin fluid communication with the area outside of catheter body 28 that isdistal to the balloon 30. In this case, the flow through channel 26 isbidirectional. The optimal channel diameter is 0.1 mm to 1 mm; howeverthis channel can be in the range of 0.05 mm to 2 mm.

FIG. 7 illustrates an exemplary embodiment of a longitudinal crosssection of the distal end of device 24 with catheter body 28, ballooninflation lumen 50, guidewire/injection lumen 52, balloon 30, valve 32and channel 26 with proximal port 54 and distal port 56. Channel 26passes through and within catheter body 28 and extends from the proximalside of balloon 30 to the distal side of balloon 30. Port 54, at theproximal end of channel 26 is in fluid communication with the outside ofthe catheter body that is proximal to balloon 30 and port 56, at thedistal end of channel 26, is in fluid communication with the areaoutside of catheter body 28 that is distal to the balloon 30. Valve 32,is shown at the opening of port 56 of channel 26. Valve 32 allows flowin the distal direction and prevents flow in the proximal direction. Inthis case, the flow through channel 26 is unidirectional. The optimalchannel diameter is 0.1 mm to 1 mm; however this channel can be in therange of 0.05 mm to 2 mm. The valve can be positioned at the proximal ordistal opening or anywhere within the channel. Location andconfiguration of the valve will determine flow direction.

Referring to FIG. 8, a longitudinal cross section of the distal end ofdevice 24 is shown with catheter body 28, balloon inflation lumen 50,guidewire/injection lumen 52, balloon 30, valve 32, channel 26 anddistal tip 6.

Referring to FIG. 9, linear cross sections through catheter body 4 andballoon 8 are shown. FIG. 9 illustrates examples of flow channelsthrough a balloon positioned on a catheter, however, variousalternatives, modifications, and equivalents may be used. FIG. 9A showscatheter 4 and balloon 8 without a channel. FIG. 9B shows catheter 4 andballoon 8 with two channels 38 through balloon 8. In this case the flowis bidirectional. FIG. 9C shows a catheter and balloon with threebidirectional channels. FIG. 9D shows a catheter 4 with a balloon 8 withtwo channels, each with a one-way valve. In this case the channel flowin each channel is unidirectional. FIG. 9E shows catheter 4 with balloon8 and three channels 38, each with an independent valve 38. The flow isunidirectional. FIG. 9F is a catheter and balloon with two channels anda single circumferential valve 33 that covers both channels 38 andallows flow in only 1 direction. FIG. 9G shows a catheter 4 and balloon8 with three channels and a single circumferential valve 33 that coversall three channels. FIG. 9H shows a catheter 5, and four bidirectionalchannels 39 that are formed by pleating balloon 36 from the outercircumference of the expanded balloon, inward toward the centralcatheter and securing the inner apex of the balloon to the catheter,thereby forming triangular channels which radiate outward from thecentral catheter, forming a “V” shape. The lower point of the ‘V” ispositioned at the catheter surface and the open end of the “V” ispositioned at the outer circumference of the circle defined by thelargest diameter of the inflated balloon. FIG. 9I shows four channels39, with a single circumferential valve 35 covering all four triangularchannels. Although the figure shows four channels, the device of thisdisclosure can have one, two, three, four or any number of channels.FIG. 9J shows a catheter 7 and a balloon 39 with four channels 37 thatare formed by pleating the balloon 39 from the inner catheter 7 towardthe outer circumference of the expanded balloon 39. FIG. 9K shows fourchannels 37 as in FIG. 9J with a single circumferential valve 39 thatcovers all four channels 37. FIG. 9L shows four channels 37 as in FIG.9J with a one piece cross-shaped flap valve 41.

While the above is a complete description of exemplary embodiments ofthe present disclosure, various alternatives, modifications, andequivalents may be used. Therefore, the above description should not betaken as limiting the scope of the disclosure, which is defined by theappended claims and the claims in any subsequent applications claimingpriority hereto.

FIG. 10 illustrates a tumor and its associated vasculature with tumor60, main artery 62, side branch artery 64, tumor artery 66, tumorcapillary 68 and antegrade arterial flow direction illustrated by arrows70.

FIG. 11 is an expanded view of FIG. 10 with tumor 60, main artery 62,side branch artery 64, tumor artery 66 and antegrade arterial flowdirection illustrated by arrows 70.

FIG. 12 illustrates injection of fluid 76 using a standardmicro-catheter 72 with tumor 60, main artery 62, side branch artery 64,tumor artery 66, guidewire 74 and retrograde arterial flow directionillustrated by arrows 70. In this instance, injection pressure and flowvolume of the fluid 76 that may contain anti-cancer drugs, radioembolicsubstances, chemoembolic substances, embolic agents or the like, throughmicrocatheter 72 is higher than the tumor vasculature can accept causinga reversal of fluid flow and blood flow in tumor artery 66, side branchartery 64 and main artery 62. This retrograde flow causes the injectedfluid 76 to enter the main artery, flowing in both directions and intothe general circulation resulting in the injected fluid traveling tonon-target tissues and organs. This unintended delivery of fluid 76 tonon-target sites is undesirable and must be avoided since it can causeserious complications. The present disclosure solves this problem bypreventing reflux and associated non-target delivery of fluid 76.

FIG. 13 illustrates catheter 4 of the present disclosure entering themain artery with balloon 8 and distal tip 6. Although the entry pointfrom outside the body is typically through the femoral artery at thegroin, any artery or vein from any location on the body can be used foraccess provided that it creates a pathway to the target vasculature.

FIG. 14 illustrates catheter 4 with balloon 8, of the presentdisclosure, following guidewire 74 into side branch artery 64.

FIG. 15 illustrates catheter 4, inside the branch artery 64 with balloon8 in the expanded configuration, channels 38 and valves 16. Valves 16are illustrated in the closed position immediately following theinflation of balloon 8.

FIG. 16 illustrates catheter 4, inside the branch artery 64 with balloon8 in the expanded configuration, channels 38 and valves 16. Valves 16are illustrated in the open position since antegrade blood flow asindicated by arrows 70 and associated blood pressure causes these valvesto open and allow the blood to continue to flow in the antegradedirection and into the tumor vasculature.

FIG. 17 illustrates the initial injection of fluid 76 into side branchartery 64 through catheter 4, channels 38 and open valves 16. When theinjection is initiated, the antegrade blood flow carries the injectionfluid 76 into the tumor vasculature including tumor arteries 66, andcapillaries 68.

FIG. 18 illustrates injection of fluid 76 at a point when fluid pressureincreases within the tumor vasculature and concomitant retrogradearterial blood flow and injection fluid flow in the direction asillustrated by arrows 70. Shown in this figure are catheter 4 of thepresent disclosure with tumor 60, main artery 62, side branch artery 64,tumor artery 66, and guidewire 74. Injection fluid 76, may containanti-cancer drugs, radioembolic substances, chemoembolic substances,embolic agents or the like, which can cause serious complications ifdelivered to non-target sites. In this case, the retrograde pressurecauses valves 16 to close and prevents the reflux of injection fluidinto the general circulation, thereby preventing complicationsassociated with delivery of injection fluid to non-target sites.

FIG. 19 illustrates a point in time following the completion of fluidinjection. At this point, the pressure in the vasculature that is thedistal to balloon 8, including side branch 64 and tumor artery 66, isreduced below normal blood pressure due to the gradual uptake of theinjected fluid into the tumor vasculature. The blood pressure on theproximal surface of balloon 8 and valves 16 cause them to open allowingantegrade blood flow to be reestablished. When this occurs, the excessfluid 76 distal to balloon 8 and within the side branch artery 64 andtumor vasculature, including tumor artery 66 and tumor capillaries 68,is flushed forward and up into the tumor vasculature, thereby enablingdelivery of the entire fluid dose and eliminating fluid reflux andassociated complications.

FIG. 20 illustrates the deflation of balloon 8 on catheter 4.

FIG. 21 illustrates the withdrawal of catheter 4 into the main artery62.

FIG. 22 illustrates another embodiment of the present disclosure asdescribed in FIGS. 6, 7 and 8. In this case valve 32 on the distal endof channel 26 of catheter 28 is in the closed position.

FIG. 23 illustrates an embodiment of FIG. 22 with valve 32 in the openposition.

A Method, according to the present disclosure is illustrated by FIGS. 13through 21; the method applies to both the embodiment illustrated inFIGS. 1B, 2, 3, 4 and 5 and the embodiment illustrated in FIGS. 1C, 6,7, 8, 22 and 23.

Referring to FIG. 24A, a longitudinal cross section of a standard singlelumen straight tip catheter 101, having a proximal and distal end, isshown with catheter body 102, and hub 105. Hub 105, positioned at theproximal end, further comprises guidewire/injection lumen 110, in fluidcommunication with a catheter lumen longitudinally oriented andextending from hub 105 and exiting at the distal end of the catheterbody 102. The proximal hub connects to a syringe or other means toinject fluids via a luer fitting, thereby allowing injection of a fluidthrough the longitudinal lumen and exit at the distal end of catheterbody 102.

Referring to FIG. 24B through 24E, longitudinal cross-sections of asequential assembly of a preferred embodiment of the present disclosureis shown. Referring to FIG. 24B, device 103 is shown, having a proximaland a distal end, catheter body 102, catheter extension 104 and hub 106.Hub 106 further comprises handle 109, guidewire/injection luer fitting110 and balloon fill luer fitting 112. Luer fitting 110 is in fluidcommunication with a first longitudinal guidewire/injection lumen ofcatheter body 102, extending to the distal end of catheter extension104, and luer fitting 112, in fluid communication with a secondlongitudinal balloon fill lumen of catheter body 102, extending to aballoon fill port located near the distal end of catheter body 102. FIG.24C further comprises nose cone 114, positioned on catheter extension104, forming balloon pocket 116 disposed between the distal end ofcatheter body 102 and nose cone 114. Further, a portion of catheterextension 104 can, if desired, extend distal to nose cone 114, therebyforming distal tip 118. FIG. 24C, further illustrates occlusion balloon120 in a radially compressed configuration and FIG. 24E illustratingballoon 120 in a radially expanded configuration. Hubs 106 can beconstructed from styrene, polyurethane, polypropylene, lipid resistantpolycarbonate, polycarbonate, Pebax (polyether block amide), of anydurometer, or any convenient material and can have any configuration,including, but not limited to, a solid structure comprising two lumensor tubular extensions of the lumens of catheter body 102, provided thatthey are in fluid communication as described above. Catheter body 102can be formed from any plastic or thermoplastic material includingpolyurethane, PTFE, polyimide, polypropylene, Pebax or the like, and cancomprise a single section or multiple sections of different diameter,durometer, braid or coil reinforcement or any convenient constructionwith a diameter of between 1 Fr and 10 Fr more typically of 2 Fr to 5Fr. Catheter extension 104 can have a diameter of 0.5 Fr to 5 Fr, moretypically of 1 Fr to 3 Fr and can be absent or can be of any length,typically 2 mm to 30 mm, more typically from 5 mm to 20 mm. If thecatheter extension 104 extends beyond nose cone 114, the section distalto the nose cone forms the distal tip 118. Distal tip 118 isadvantageous when injecting deep into the tumor vasculature is desiredand will also help tracking of device 103 over a guidewire around sharpcorners and through a tortuous vasculature path. Nose cone 114 can bemade from any polymer or metal or can be formed from a radiopaque markerband. Balloon pocket 116 can be of any length between 2 mm and 50 mm,more typically between 5 mm and 20 mm. Occlusion balloon 120 has alongitudinal length of 1 mm to 30 mm, more typically of 2 mm to 10 mmand a diameter of 1 mm to 50 mm, typically from 2 mm to 10 mm and can becomposed of silicone, polyurethane, polyethylene, PET (polyethyleneterephthalate), nylon or the like and can be of any configuration or ofany length or shape and can be glued, chemically bonded, heat bonded, RFwelded, sonically fused, compressed or crimped under a collar tocatheter 102 or catheter extension 104.

Referring to FIG. 25A, a distal section of a device 128 of a preferredembodiment of the present disclosure is shown and includes catheter body102, catheter extension 104, nose cone 114, balloon pocket 116, balloonfill lumen 124, guidewire/injection lumen 126 and radially compressedballoon 120. Referring to FIG. 25B, balloon 120 is shown in its radiallyexpanded configuration. Balloon fill lumen 124 can be of any convenientshape including but not limited to round, semicircular, or crescent orany shape, typically optimized to provide maximum area and flow rate.Guidewire/injection lumen 126 is typically round, having a diameter of0.005″ to 0.1″, more typically from 0.01″ to 0.05″; however, it can beof any desirable shape.

Referring to FIG. 26A, the distal end 133 of an embodiment of thepresent disclosure is shown with catheter body 102, catheter extension104, nose cone 114, balloon pocket 116, balloon fill lumen 124,guidewire/injection lumen 126 and radially compressed balloon 120. Inthis instance, the balloon pocket 116 is formed between a proximalcollar 130 and a distal collar 114, tapered forward thereby forming anose cone. The balloon bonding tails 115 can be bonded within the pocketor compressed or bonded under collars 114 and 130. Distal collar 130 cancomprise a metal, such as a radiopaque marker band or a plastic such asheat shrink tubing and can be 1 mm to 20 mm in length, more typicallyfrom 2 mm to 10 mm. Balloon fill lumen 124 is shown traveling underballoon pocket 116 and ending at its distal end. Guidewire/injectionlumen 126 is shown traveling longitudinally through catheter 102 andcatheter extension 104, ending at the distal end of the catheter.Balloon 120 is shown tucked into pocket 116 with outer diametersubstantially no larger than the outer diameter of catheter body 102.FIG. 26B shows the same construction as FIG. 26A with balloon 120 in itsradially expanded configuration.

Referring to FIG. 27A, a view of distal section 133 is shown and furtherillustrates that the profile of a preferred embodiment of the presentdisclosure, including the radially compressed balloon 120, the distalcollar 114 and the proximal band 130, have an outer diameter equal to orless than that of catheter body 102. FIG. 27B shows the sameconstruction as FIG. 27A with balloon 120 expanded from pocket 116 andbetween collars 114 and 130.

Referring to FIG. 28A, a distal section of an alternate embodiment 135of the present disclosure is shown with outer catheter 119, innercatheter 127, nose cone 125, radially constrained balloon 131 andcatheter channels 123. The outer catheter 119 is adapted over innercatheter 121, the catheters configured to provide a radially distributedspace between inner and outer catheters extending longitudinally alongthe length of device 135. Outer and inner catheters can have a length of10 cm to 250 cm, more typically 50 cm to 150 cm and a diameter ofbetween 0.5 Fr and 10 Fr more typically of 1 Fr to 5 Fr. Inner catheter127 can have a length less than, equal to, or longer than the outercatheter 119, however in the present figure, inner catheter 127 is shownto be longer than outer catheter 119, its distal end forming thecatheter extension 127. Nose cone 125 is disposed along the distalextension of inner catheter 127 at some distance from the distal end ofouter catheter 119, the distance being 2 mm to 50 mm, more typicallybetween 5 mm and 20 mm. The balloon pocket is formed between the distalend of catheter 119 and the proximal end of nose cone 125. FIG. 28Bshows an end view of outer catheter 119, disposed over inner catheter127, with radially configured channels 123 and stand-offs 127 disposedbetween outer catheter 119 and inner catheter 127. Four channels areillustrated, however device 135 can have 0, 1, 2, 3, 4 or any number ofchannels and stand-offs, the stand-offs defining the outer edges of thechannels 123 and can be formed on either the inner or outer catheterwith a height limited only by the diameter of the inner and outercatheters and space there between. Although stand-offs are shown, theyare not required, provided that the inner catheter OD is smaller thanthe outer catheter ID, thereby forming a space between the inner andouter catheters which allow fluid to flow longitudinally along device135. Device 135 can comprise single layer inner and outer catheters orone or both can have multiple layers. In a preferred embodiment, outercatheter 19 is a three layer construction with an outer Pebax layer, acentral polyimide layer including reinforcement such as a coil or braidand an inner Teflon layer. Inner catheter 127 is a single layer of lowfriction tubing, or tubing of similar construction to that described forthe outer catheter 119. FIG. 28C shows a longitudinal view of device 135with outer catheter 119, unexpanded balloon 131, nose cone 125 and acatheter extension of inner catheter 127. Balloon 131 is shown tuckedwithin a pocket formed between the distal end of catheter 119 and theproximal end of nosecone 125. FIG. 28D shows a longitudinal crosssection of device 135, showing balloon inflation channel 123 disposedbetween outer catheter 119 and inner catheter 121. In this instance, thedistal end of balloon 131 is shown inserted into the proximal end ofnose cone 125; however both proximal and distal balloon tails can bebonded directly to inner catheter 127, reflowed into catheter 119 ornose cone 125 or by any means, provided that the balloon tails arepositioned approximately below the outer diameter of catheter 119.

Referring to FIG. 29A though FIG. 29E, examples of balloonconfigurations that may be used in the device of the present disclosureare shown which can be compliant or noncompliant, dilation or occlusionand can be made from any material including, but not limited to,silicone, polyurethane, polyethylene, PET (polyethylene terephthalate)and nylon.

Referring to FIG. 30, a surface view of balloon 160 is shown withone-way bypass channels 162 and valves 164, the balloon is described indetail in patent application No. 61/821,058.

Balloon 160 and valves 164 allow flow from the compartment proximal tothe proximal surface of balloon 160 to the compartment distal to thedistal surface of balloon 160 (antegrade flow) and prevents flow fromthe compartment distal to the distal surface of balloon 160 to thecompartment proximal to the proximal surface of balloon 160 (retrogradeflow). Balloon 160 can be disposed on the catheter of the presentdisclosure and held within a balloon pocket as illustrated in FIGS.24-29 and enable antegrade injection of therapeutic agents from withinan artery and into a target while maintaining normal (antegrade) bloodflow through channels 162 of balloon 160 and prevent retrograde flow(reflux) of therapeutic agents backward over the catheter, even whenpressure distal to balloon 160 is elevated above systolic and/or meanarterial pressure.

Referring to FIG. 31, a cross section of balloon 160 is shown withchannels 162 and microvalves 164, positioned within channels 162.

FIG. 32 shows an example of a sequential assembly of an embodiment ofthe present disclosure. Referring to FIG. 32A, catheter 170 of device168 is shown. FIG. 32B illustrates a first step in the construction ofdevice 168 whereby a balloon pocket 172 is formed about a distal sectionof catheter 170 and a second step, as in FIG. 32C, whereby a roundeddistal end 174 of catheter 170 is formed and a third step as in FIG. 32Dwhereby a balloon 176, with bonding tails 178 is disposed within pocket172 of catheter 170 and a fourth optional step whereby catheter 170 orother material is reflowed at position 180 over balloon tails 178. FIG.32F illustrates balloon 176 in its radially expanded configuration withballoon pocket 172 and tails 178 bonded in pocket 172 without beingcovered by reflow or other means.

Referring to FIG. 33, three alternate embodiments of the presentdisclosure are illustrated. FIG. 10A shows device 173 with catheter 181,balloon pocket 177, radially constrained balloon 178, catheter extension171 and nose cone 182. FIG. 33B shows device 173 with radially expandedballoon 178 and bonding tails 183 bonded within balloon pocket 177. FIG.33C illustrates device 175 with nosecone 182 and proximal bonding tail191 reflowed into catheter 181 at position 179 and the distal balloonbonding tail 193 reflowed into or under nose cone 182 to catheterextension 171 at location 184. FIG. 33D illustrates device 179 withcatheter 181, balloon 178, nose cone 182 and collar 186. Balloon 178 hasa proximal tail 191 positioned under collar 186 and distal balloon tail193 reflowed or bonded to catheter extension 171 and under nose cone 182or into nose cone 182. FIG. 33E shows device 179 with balloon 178expanded from within the balloon pocket formed between collar 186 andnose cone 182.

FIG. 34 shows yet another embodiment of the present disclosure with twoballoons 188 and 189, catheter 183, balloon pockets 194 and 190, reflowareas 192 and nose cone 189. Although the example of FIG. 34 shows bothballoon 188 and 189 positioned within pockets 194 and 190, only oneballoon need be positioned within a pocket.

FIG. 35 shows still another embodiment of the present disclosure withballoon 196 containing channels 195 and 197, valve 198 in the closedorientation, valve 199 in the open orientation, collar 183, nose cone1102 and reflow area 1100. Although valve 198 is shown closed and valve199 is shown open, they will typically act in unison and all either besimultaneously open or closed.

FIG. 36 shows still another embodiment of the present disclosure whichincludes two pressure sensors, positioned distal and proximal to balloon1110, although a single pressure sensor positioned either distal orproximal to the balloon can be used. These pressure sensors can be usedto monitor and, in conjunction with a syringe, control injectionpressure either manually of by an automated means. Alternately pressureproximal or distal to the occlusion balloon can be measured through thecatheter using an external pressure gauge (1113), the distal pressurebeing measured via the guidewire/injection lumen 1105 or any othercatheter lumen or other tube. The pressure gauge can be connected to apump, via a processor, allowing the pump to achieve a defined pressureor be programmed to a specific set of pressures, volumes and/or flowrate as a function of time.

Referring to FIG. 37, four embodiments of balloon configurations areshown. FIG. 37A, shows device 1115 with balloon 1117 and catheter 1116.Balloon 117 in a radially expanded configuration, occupies only part ofthe circumference of catheter 1116. FIG. 37B illustrates device 1118with catheter 1119 and balloons 1121 whereby the four balloons 1121, inradially expanded configurations are arranged circumferentially aboutcatheter 1119, each occupying a part of the overall outer circumferenceof catheter 1119. FIG. 37C illustrates device 1123, with catheter 1125and balloon 1127 in a radially expanded configuration, whereby balloon1127, in a radially constrained configuration is positioned within apocket of catheter 1125 and the radially outermost part of balloons 1127is positioned approximately at or below the outer diameter of catheter1125. FIG. 37D illustrates device 1131 with catheter 1135 and balloons1137 in a radially expanded configuration, whereby balloons 1137, in aradially constrained configuration are positioned within a pocket ofcatheter 1135 and the radially outermost part of balloons 1137 areapproximately positioned at or below the outer diameter of catheter1135.

Referring to FIG. 38, an anatomical structure 1120 is shown with mainartery 1122, right artery 1124, left artery 1126, right capillaries1128, left capillary 1129, arterial side branch 1136, vein 1130,arteriovenus shunt 1132, tumor 1133, blood flow directional arrows 1134,standard straight tip catheter 1138, and embolization particles 1125.FIG. 38A illustrates the beginning of a transarterial embolization (TAE)procedure wherein the embolization particles 1125 are exiting the distalend of catheter 1138 and are carried by forward (antegrade) blood flowinto tumor 1133 in a delivery method that is completely mediated byblood flow and normal blood pressure (flow mediated delivery). Capillarybeds 1128 and 1129 of tumor 1133 begin to fill with embolic particles1125 and arteriovenus shunt 1132 carries particles into vein 1130causing antegrade reflux and non-target embolization. The flow throughthe arteriovenous shunt 1132 is rapid since the arterial pressure issignificantly higher than venous pressure. Referring to FIG. 38B,continued injection of particles 1125 from the distal end of standardstraight tip catheter 1138 results in the packing of particles andembolization of the distal ends of capillary beds 1128 and 1129. Distalcapillary embolization causes the flow through arteriovenous shunt 1132to stop and pressure to build in left artery 1126. As embolizationprogresses, the back pressure in artery 1126 continues to rise untilembolic particles reflux in the retrograde direction 1142 causingnon-target embolization of the right artery 1124, arterial side branch1136 and main artery 1122. This situation can cause non-targetembolization, loss of an unknown amount of particles, delivery of anunknown and irreproducible dose and non-optimal distribution of embolicparticles in the tumor vasculature. In this instance, both antegrade andretrograded reflux can occur.

Referring to FIG. 39, anatomical structure 1120 is shown as in FIG. 38.In this instance, a balloon 1141, with channels 1143 and one-way valves(FIGS. 30 and 31) is positioned about the distal end of catheter 1139.Balloon 1141, so constructed, will allow only antegrade (normal) flowand prohibit retrograde flow. Referring to FIG. 39A, balloon 1141 isshown in its radially expanded configuration and blood is flowingthrough balloon channels 1143 as indicated by blood flow arrow 1134 andinto the vasculature of tumor 1133. Embolic particles 1125 are releasedfrom the distal end of catheter 1139 and carried forward by blood flowinto capillaries 1128 and 1129. Capillary beds 1128 and 1129 of tumor1133 begin to fill with embolic particles 1125 and arteriovenus shunt1132 carries particles into vein 1130 causing antegrade reflux andnon-target embolization. The flow through the arteriovenous shunt 1132is rapid since the arterial pressure is significantly higher than venouspressure. Referring to FIG. 39B, continued injection of particles 1125from the distal end of balloon catheter 1139 results in the packing ofparticles and embolization of the distal ends of capillary beds 1128 and1129. Distal capillary embolization causes the flow througharteriovenous shunt 1132 to stop and pressure to build in left artery1126. As embolization progresses, the pressure in artery 1126 continuesto rise, however the valves of balloon 1141 close and prohibitretrograde reflux. In this instance, continued injection will increasethe packing pressure of particles 1125 and can increase packing densityand increase flow into distal locations in the margins of a tumor orother structure thereby improving particle distribution throughout thetarget vasculature. As part of the present method, pressure distal tothe balloon can be regulated between systolic and/or mean arterialpressure and any pressure above that pressure, provided that it iswithin a range that is safe for the patient. By way of example,injection pressure can be low at the onset of the embolization procedureand increased at some point thereafter to a pressure greater thansystolic and/or mean arterial pressure. Such a point may, for example,be chosen to coincide with the stoppage of flow through arteriovenousshunt 1132. This method may improve particle distribution and packing.Alternately, the injection pressure through catheter 1139 can be high atthe onset, thereby forcing particles rapidly into the distal section ofcapillaries 1128 and 1129 and hasten embolization of arteriovenous shunt1132, thereby reducing antegrade reflux. Alternately, according to thismethod, a low to high pressure gradient or a high to low pressuregradient can be used. The aim for the use of a pressure mediateddelivery of particles is to optimize for a low level of antegradereflux, substantial elimination of retrograde reflux, high particledistribution and high particle density. A pressure sensor as in FIG. 36can be used on the proximal and/or distal side of balloon 1142 tomonitor pressure and enable a selection of a procedural end point basedon a definitive pressure reading.

Referring to FIG. 40, anatomical structure 1120 is shown as in FIG. 38.In this instance, an occlusion balloon 1142 is positioned about thedistal end of catheter 1140. Referring to FIG. 40A, balloon 1142 ofcatheter 1140 is shown in a radially expanded configuration. Sinceexpanded balloon 1142 completely occludes artery 1126, all arteries andcapillaries distal to the balloon are isolated from the main artery1122, right artery 1124 and side branch artery 1136 thereby causingblood pressure distal to the balloon to drop from approximately normalarterial pressure of about 80 mmHg to a pressure in the range of 0-50mmHg. When this happens, blood flow through the arteriovenous shunt 1132can reverse as shown by blood flow arrow 1135, or the antegrade flowslowed or stopped. Referring to FIG. 40B, initial injection of particles1125 will be against a pressure, with a minimal antegrade flow or into aflow stasis. Retrograde pressure flow against the particle injection canresult from the flow of venous blood from vein 1130, througharteriovenus shunt 1135 and into the arterial capillary 1129 or fromarteriovenous capillary beds associated with capillaries 1128. Asparticles 1125 are injected, they fill capillaries 1128 and 1129;however, particles cannot easily flow through arteriovenous shunt 1132because of the reversal or slowing of flow and pressure. Continuedinjection can result in embolization of the distal portion of capillary1129 and blockage of arteriovenous shunt 1132 with concomitant reductionor elimination of antegrade reflux. Increasing injection pressurethrough catheter 1140 following embolization of arteriovenous shunt1132, can result in a high levels of particle density and distribution.Alternately, according to this method, a gradient can be used. Theprofile of the pressure gradient can be any function of time andpressure including, but not limited to, a linear or step function fromlow to high, high to low, alternating high to low and low to high or anyother function and can be administered manually, in a semi-automatedmanner or using a programmable delivery means. Alternately according tothis method, a pressure sensor as in FIG. 36 can be used on the proximaland/or distal side of balloon 1142 to monitor pressure and select aprocedural end point based on a definitive pressure reading. Referringnow to FIG. 40D, the injection through catheter 1140 into tumor 1133 canbe accomplished using an automated pump/pressure monitor system wherebythe pressure distal to occlusion balloon 1142 is measured on gauge 1152,the pressure reading transferred through connection 1154 to pump 1150which controls the injection of anti-tumor agents from syringe 1156.Pump 1150 can be controlled manually or programmed to any function offlow rate, time and/or pressure. The endpoint can be selected at anydesirable pressure.

The aim of the present method is to eliminate retrograde reflux, reduceor eliminate antegrade reflux, control the particle density anddistribution, deliver an optimal dose, enable a defined pressureendpoint, improve efficacy and reduce toxicity.

Referring to FIG. 41A, a longitudinal cross section of a catheter isshown with proximal and distal ends, catheter body 204, distal tip 203and proximally disposed hub 206. Catheter body 204 has two lumens thatare in fluid communication with hub 206, a first lumen extending fromport 208 of hub 6 to the distal tip 203 of catheter 204 whereby fluidcan be injected from the proximal hub 206 and exit at the distal tip 203of catheter 204 and a second lumen extending from port 210 of hub 206 toan intermediate location at some distance from the distal tip 203 ofcatheter 204, the second lumen adapted to communicate with a balloon forinflation and deflation.

Referring to FIG. 41B, a longitudinal cross section of a firstembodiment of the present disclosure is shown with proximal and distalends, catheter body 204, distal tip 203, and two layered occlusionballoon 214 with channels 205 and valves 207 and proximally located hub206. Although balloon 214 is shown with two channels, each with a valve,balloon 214 can have 1, 2, 3, 4 or any number of channels and any numberof valves or be without valves. In this instance, the valveconfiguration allows fluid to flow from the proximal side of balloon 214to the distal side of balloon 214 and to restrict flow from the distalside of balloon 214 to the proximal side of balloon 214; however, theopposite valve orientation and flow direction is also part of thepresent disclosure. Catheter body 204 can have a diameter of between 1Fr and 10 Fr, more typically 2 Fr to 5 Fr and a length of 10 cm to 250cm, more typically 50 cm to 150 cm. Two layered occlusion balloon 214can be from 1 mm to 30 mm in diameter, more typically 2 mm to 10 mm indiameter, in its radially expanded configuration.

Referring to FIG. 41C, an alternate embodiment of the device of thepresent disclosure is shown, having catheter body 218, distal tip 209,hub 206 and umbrella shaped occlusion structure 220. When in itsradially expanded configuration, the occlusion structure will completelyocclude the flow of the vessel. The umbrella shaped occlusion structure220 is positioned at some distance from the distal end of catheter 216and forms an umbrella shaped structure disposed circumferentially aboutcatheter 216 with its outer diameter in contact with the vessel.Umbrella shaped occlusion structure 220 can be from 1 mm to 30 mm indiameter more typically 2 mm to 10 mm in diameter when in its radiallyexpanded configuration and a longitudinal thickness of 0.25 mm to 10 mm,more typically 0.5 mm to 2 mm. Umbrella shaped occlusion structure 220is shown with its closed end attached to the catheter distal to the openend of the V shape; however, it can be positioned in the oppositeorientation or it can be positioned at a 90 degree angle with respect tocatheter body 18.

Referring to FIG. 41D, device 222 of the present disclosure is shownhaving catheter 218, distal tip 209, hub 206, and a unidirectionalumbrella occlusion structure 224 with channels 230 and valves 228.Occlusion structure 224 will allow proximal to distal flow and preventdistal to proximal flow.

Referring to FIG. 41E, device 232 is shown with catheter body 234,catheter distal extensions 235 and distal tip 211. Catheter extension235 can have a diameter of 0.5 Fr to 5 Fr, more typically of 1 Fr to 3Fr and can be absent or can be of any length, typically 2 mm to 30 mm,more typically from 5 mm to 20 mm.

Referring to FIG. 41F, a preferred embodiment of the present disclosureis shown with catheter body 237, catheter extension 235, distal tip 211,nose-piece 241 and two layered occlusion balloon 243 in its radiallyexpanded configuration. In this instance, two layered occlusion balloon243 is disposed within a pocket formed on distal catheter extension 235and between the distal end of catheter body 237 and the proximal end ofnose-piece 241. The nose piece can be a tapered nose cone, a distallyrounded piece of tubing or catheter, a blunt tube or any structure witha diameter equal to less than the catheter body. When in the radiallyconstrained configuration, the outer diameter of the two layeredocclusion balloon 243 has an outside diameter that is about equal to theouter diameter of the catheter body 237.

Referring to FIG. 41G, yet another embodiment of device 245 of thepresent disclosure is shown, having catheter body 247, distal tip 234,nose-piece 241, proximal hub 206 and unidirectional umbrella shapedocclusion structure 224 with channels 230 and valves 228. In thisinstance, unidirectional umbrella occlusion structure 224 with channels230 and valves 228 is disposed within a pocket formed on distal catheterextension 234 and between the distal end of catheter body 247 and theproximal end of nose-piece 241. The nose piece 241 can be a tapered nosecone, a radiopaque marker band, a distally rounded piece of tubing orcatheter, a blunt tube or any structure of about equal diameter to thecatheter body. When in the radially constrained configuration, theunidirectional umbrella shaped occlusion structure 224 has an outsidediameter that is about equal to the outer diameter of the catheter body247.

Referring to FIG. 42, four views of a preferred embodiment of theunidirectional occlusion structure of present disclosure is shown. FIG.42A illustrates a two layered unidirectional occlusion structure 236 inits radially expanded configuration (also seen in FIGS. 41B and 41F),having a proximal end 238, a distal end 240, balloon 242, balloon sheath244, channel 246, valve structure 250, outer balloon sheath tail 254,balloon tail 256, flow direction arrow 252 and flow exit 248. Whenocclusion structure 236 is disposed on a catheter as in FIG. 41F, fluidflows in the proximal to distal direction (antegrade) as indicated byarrow 252 through channel 246 and valve 250 and exits out the distalflow exit 248. The antegrade fluid pressure on the inner surface ofballoon sheath 244 at the distal end of channel 246, causes distallydirected displacement or deflection of the inner surface of balloonsheath 244 at valve 250, thus allowing fluid to pass through flow exit248. When flow is reversed, fluid pressure on the outer distal surfaceof balloon sheath 244 at valve 250 causes the balloon sheath 244 topress against the distal surface of balloon 242, closing valve 250 andpreventing retrograde flow. Placing the unidirectional occlusionstructure 236 in the opposite direction on the catheter will result indistal to proximal flow and prohibit proximal to distal flow. Althoughthe occlusion structure of FIG. 42A is shown with two layers includingan inner balloon and an outer sheath, it is understood that the sheathneed not be present and a balloon with channels from the proximalsurface to the distal surface is considered part of the presentdisclosure. Balloon 242, including channels 246 can be formed bymolding, extruding, vacuum forming or otherwise shaping a material toinclude the desired number and configuration of channels. Alternately, astandard balloon, including but not limited to, round or oval, can bemodified to achieve proximal to distal channels. One method to modify aballoon is by forming longitudinal pleats circumferentially oriented,thereby forming V shaped channels that extend from the proximal surfaceof the balloon to the distal surface of the balloon. Placing a sheathover such a modified balloon in the same manner as described above wouldgive the same result as the balloon shown in FIGS. 42A through 42D.

Referring to FIG. 42B, a side view of the unidirectional occlusionstructure 236 of this disclosure is shown with proximal end 238 distalend 240, balloon 242, balloon sheath 244 and flow direction arrow 252.

Referring to FIG. 42C, a proximal view of the unidirectional occlusionstructure 236 is shown with proximal end 238, distal end 240 andchannels 246.

Referring to FIG. 42D, a distal surface view of the unidirectionalocclusion structure 236 is shown with proximal end 238, distal end 240and flow exit 248. Flow exit 248 is formed as a space between balloontail 256 and balloon sheath 254. It is also possible to terminateballoon sheath 244 immediately below channels 246 forming a valve 250that does not include balloon sheath tail 254.

Referring to FIG. 43, an illustration of a prototype of theunidirectional occlusion structure 236 is shown in its radially expandedconfiguration with proximal end 238, distal end 240, balloon sheath 244,balloon 242 (positioned inside balloon sheath 244), and channel 246.This device was tested and will withstand at least 220 mmHg against itsdistal surface without retrograde flow.

Referring to FIG. 44, device 60 illustrates the unidirectional occlusionstructure 272 in a radially constrained configuration adapted to thedistal extension 267 of a catheter 265 with distal end 262, proximal end264, proximal collar 266, distal collar 268 (formed into a nose cone)and device pocket 270. Proximal collar 266 and distal collar 268 cancomprise a metal, such as a radiopaque marker band, heat shrink tubingor any plastic material such as polyurethane, polyethylene, polystyrene,acetal, PTFE, nylon or the like, and can be 1 mm to 20 mm in length,more typically from 2 mm to 10 mm in length. In this instance,circumferentially oriented occlusion structure 272 is held within pocket270 of catheter 265, with an outer diameter approximately equal to theouter diameter of catheter 265.

Referring to FIG. 44B, device 260 is shown with unidirectional occlusionstructure 272 in its radially expanded configuration with proximal end264, distal end 262, balloon 242, balloon sheath 244, valve 250, flowexit 248, channel 246, flow arrow 252, proximal collar 266, distalcollar 268, catheter 274, balloon fill lumen 270 and guidewire/injectionlumen 276. In this instance, there is no distal balloon sheath tail, theballoon sheath terminating on the balloon surface just below channel 246and above the perimeter of catheter extension 267, thereby positioningthe flow exit between the termination of the balloon sheath and thecatheter.

Referring to FIG. 45A, device 280 is shown with catheter 282 and anumbrella shaped structure occlusion structure 2284 in its radiallyexpanded configuration, whereby the umbrella shaped occlusion structure284 is oriented circumferentially about catheter 282 such that its outercircumference is 360 degrees about catheter 282. When device 280 isplaced in an artery or vein and umbrella shaped occlusion structure 284is placed in its radially expanded configuration, the outer perimeter ofocclusion device 284 will be at least in contact with the interior ofthe vessel wall and substantially occlude flow. FIG. 45A shows occlusionstructure 284 in forward V orientation and FIG. 45B shows device 282with the umbrella shaped occlusion device 288 in a reverse Vconfiguration. The occlusion structure of the present disclosure canalso have a 90 degree orientation with respect to the catheter when inits radially expanded configuration.

Referring to FIG. 46A, device 290 is shown with proximal end 292, distalend 294, catheter 296, two-way occlusion structure 299 in its radiallyexpanded configuration, frame 298 and channels 2100, whereby fluid canflow from proximal to distal or distal to proximal through channels2100. Although two channels are shown, two-way occlusion structure 298can have 1, 2, 3 or any number of channels.

Referring to FIG. 46B, device 2102 is shown with proximal end 2104,distal end 2106, catheter 2108, and unidirectional umbrella shapedocclusion device 2110 comprising, frame 2111, channels 2112 and radialvalve 2114, whereby fluid will flow from proximal to distal (antegrade)only, retrograde flow being prohibited by radial valve 2114. Althoughdevice 2102 will allow only antegrade flow, if desired, device 2110 ofapparatus 2102 can be configured to allow only retrograde flow and/orhave a forward V configuration as shown, or, if desired, a reverse Vconfiguration or an orientation 90 degrees with respect to catheter2108.

The frames 298 and 2111 of occlusion structure 2110 can be made ofmetal, such as shape memory metals nitinol or elgiloy, or plastic suchas polyethylene, polyurethane, polystyrene, PTFE, acetal and nylon orelastic materials such as silicone or fabrics such as cotton and rayonand can include a mesh, a wire frame, a diaphragm and can be pleated orotherwise folded or can be any other convenient structure or materialprovided that it is of sufficient strength and porosity to occludeelevated vascular pressures and capable of integrating channels andvalves. Valve 114 can be made from flexible or rigid plastics includingpolypropylene and polyurethane, elastomeric materials such as siliconeand can have a configuration including a flap, sock, cone, duck bill anddiaphragm or the like with a thickness of 1 mil to 50 mil, moretypically 2 mil to 10 mil.

Referring to FIG. 47A, a distal surface view of a unidirectionalocclusion structure 2120 of the present disclosure is illustrated withthe catheter 2122 (extending forward), device frame 2124, radial valve2125 and channels 2126 disposed under radial valve 2125. As shown,radial valve 2125 extends radially outward from catheter 290 and coversall four valves. Four channels are shown in this example; however, anynumber of channels can be used. This configuration allows flow from theproximal surface to the distal surface of unidirectional umbrella shapedocclusion structure 2120; however, the reverse flow is also possible.

FIG. 47B illustrates another embodiment of the present disclosurecomprising unidirectional umbrella shaped occlusion structure 2128 withcatheter 2130 (extending forward), device frame 2132, valves 2136 andchannels 2134 disposed under valves 2136. In this instance, each channelhas a separate valve and although four channels and valves are shown,the device of this disclosure can have any number of channels and valveslimited only by the size of the valve and channel and the area of theframes 2124 and 2132. This unidirectional configuration allows flow fromthe proximal surface to the distal surface of umbrella shaped occlusionstructure 2128; however, the opposite flow can be easily achieved bychanging the flow direction of the valves or rotating the unidirectionalocclusion device 180 degrees on catheters 2122 and 2130.

FIGS. 48A and 48B illustrate a prototype micro-valve 2140 configuredfrom 5 mil polyurethane material. This device was tested and willrestrain a fluid pressure of at least 220 mmHg applied against itsdistal surface.

Referring to FIG. 49A, device 2142 is shown with triangular shapedocclusion structure 2145 in its radially expanded configuration andadapted to catheter 2144 whereby the occlusion structure 2145 has frame2146 oriented circumferentially about catheter 2144 such that its outercircumference comprises 360 degrees. When device 2142 is placed in anartery or vein, frame 2146 is placed in its radially expandedconfiguration and the outer perimeter of device frame 2146 will be atleast in contact with the interior of the vessel wall and at leastsubstantially occlude flow.

Referring to FIG. 49B, device 2148 is shown with catheter 2150 and aunidirectional triangular shaped occlusion structure 2151 comprisingframe 2152, channels 2154 and radial valve 2158. Although reference hasbeen made to a unidirectional occlusion valve with an umbrella shape ora triangular shape, it is understood that any shape including, but notlimited to, rectangular, oval, conical, and round can be used. Yetanother construction of a unidirectional occlusion structure is adilation or occlusion balloon or any other medical balloon disposed withchannels and valves, the valves extending from a proximal surface to adistal surface.

Referring now to FIG. 50A to 50C, a method of deploying an occlusionstructure 2191 from a radially constrained configuration to a radiallyexpanded configuration and then returning it to the constrainedconfiguration is shown. FIG. 50A shows a longitudinal cross section ofdevice 2180 with a proximal end 2182, a distal end 2184, outer catheter2186, inner catheter 2188, nose cone 2190 and radially constrainedunidirectional occlusion structure 2191 with frame 2192, valve 2194, andframe attachment point 2196. Unidirectional occlusion structure 2191 isattached to inner catheter 2188 at attachment point 2196 wherebyocclusion device 2191 is preloaded with a force which encourages itsdistal end to pivot proximally outward at attachment point 2196. In thisinstance, the outer catheter 2186 constrains occlusion structure 2191against the preloaded force. Device 2180 is first positioned in thevasculature at or in the vicinity of a target structure.

Referring to FIG. 50B, outer catheter 2186 is retracted proximally asshown by arrow 2200 while the inner catheter 2188 is held stationary,thereby removing the constraint on occlusion structure 2191, allowing itto pivot outward and in a proximal direction at attachment point 2196and into its radially expanded configuration. Frame 2192 can be madefrom a memory metal such as nitinol or elgiloy and pre-formed atattachment point 2196 to the radially expanded configuration therebypre-loading an outward force on occlusion structure 2191 as it is movedto its radially constrained configuration. If a braided nitinol tube isused, it can be pre-formed into a radially expanded configurationwhereby occlusion structure 2191 is oriented circumferentially aboutcatheter 2144 with an outer circumference of 360 degrees. As in thisexample, the mesh can be coated with polyurethane, PTFE, silicone or thelike and channels formed through the mesh and valves placed over thechannels.

Referring to FIG. 50C, outer catheter 2186 is retracted distally whileholding inner catheter 2188 stationary thereby pivoting frame 2192distally at attachment point 2198 and placing occlusion structure 2191in its radially constrained configuration.

Referring to FIG. 51, an anatomical structure 2200 is shown with mainartery 2202, right artery 2204, left artery 2206, capillaries 2208,tumor 2209 and blood flow directional arrows 2212. FIGS. 51A-51Eillustrates a method of the present disclosure wherein a tumor isembolized with drug eluting beads as in Transarterial Chemoembolization(TACE).

In a first step, device 2211, comprising a two lumen catheter 2214 and aradially constrained unidirectional balloon occlusion structure 2216(also in FIG. 42), is advanced over a guidewire 2213 using lumen one(guidewire/injection lumen) of catheter 2214 from an entry point on thesurface of the body, usually the femoral artery at the groin, andpositioned at, or in the vicinity of, an artery feeding a tumor as inFIG. 51A. As indicated by arrows 2212, the blood flows in an antegradedirection over device 2211 and into capillaries 2208 of tumor 2209.

In a second step, the unidirectional balloon occlusion structure 2216 isplaced in a radially expanded configuration by inflating the innerballoon of the two layered device of FIG. 42 using the second lumen ofcatheter 2214 (balloon inflation lumen) as seen in anatomical FIG. 51B.When placed in a radially expanded configuration, normal blood pressurebetween about 80 mmHg and 130 mmHg urges valves 2217 of occlusionstructure 2216 to the open position, thereby allowing antegrade bloodflow through channels 2219 and into the capillaries 2208 of tumor 2209.

FIG. 51C illustrates a third step whereby chemoembolization particles2218 are beginning to be injected into left artery 2206 and capillaries2208 of tumor 209. At this point, valves 2217 of unidirectionalocclusion structure 2216 are in the open position and blood is flowingin the antegrade direction through channels 2219 which continues tocarry chemoembolization particles 2218 into the vasculature of tumor2209.

Referring to FIG. 51D, a fourth step is illustrated wherebychemoembolization particles 2218 begin to embolize the distal ends ofcapillaries 2208, increasing pressure in the proximal section ofcapillaries 2208 and left artery 2206. This back pressure causes bloodflow and chemoembolization particles 2218 to flow in a retrogradedirection; however, the back-pressure in left artery 2206 urges valves2217 to close, thereby maintaining particles 2218 in the vascularcompartment distal to occlusion device 2217. Using currently availablestraight tip catheters, the chemoembolization procedure would beterminated at this point since particles would reflux backward over thecatheter and into the general circulation causing non-targetembolization and associated complications.

FIG. 51E illustrates a fifth step, not possible using present catheters,whereby embolization particles continue to be injected, withoutretrograde reflux, and further fill the vasculature of the tumor withparticles 2218. This method can both prevent the complicationsassociated with retrograde reflux and allow more particles to enter thetumor.

FIG. 51F is a final step in the present method whereby occlusionstructure 2216 is placed in a radially constrained configuration anddevice 2211 is withdrawn from the body over guidewire 2213.

Although particular mention has been given to a device that is capableof transitioning from a radially constrained configuration to a radiallyexpanded configuration, such a transition is not required. Aunidirectional occlusion structure of the present disclosure can beconfigured in a permanently expanded configuration. In this instance,the occlusion structure may be a highly flexible material such as a lowdurometer plastic or rubber or a flexible mesh or any material orconstruction that provides sufficient strength and flexibility tonavigate through vasculature and to a target and provide unidirectionalocclusion.

Referring to FIG. 52, distal section 302 of a device is shown withdistal end 303, proximal end 304, catheter body 306, distal tip 308,nose cone 310, partial occlusion balloon 312 in a fully expandedconfiguration, channel 314 and one-way valve 316. In this embodiment,flow is permitted in the proximal to distal direction through channel314 and restricted, by one-way valve 316 to flow proximally. Partialocclusion balloon 312 can be any shape and diameters from 1 mm to 30 mmmore typically from 2 mm to 10 mm.

Referring to FIG. 53, a longitudinal section 320 of a distal section ofthe device of the present disclosure is shown with catheter body 306distal tip 308, nose cone 310, radially constrained balloon 322,proximal balloon pocket boundary 324 and distal balloon pocket boundary326. Radially constrained balloon 322 sits within the pocket defined bythe distal end of catheter 306 at boundary 324 and the proximal end ofnosecone 310 at boundary 326. The outer diameter of the constrainedballoon is approximately equal to the outer diameter of catheter body306. This allows the balloon to sit within the pocket and maintain thecatheter at a desirable minimal diameter.

Referring to FIG. 54A, a distal section 330 of the device of the presentdisclosure is shown with catheter body 306, catheter extension 307,distal tip 308, nose cone 310, balloon pocket 332, guidewire andinjection lumen 334 and balloon inflation lumen 336. The catheter body306 has a diameter of 0.25 mm to 5 mm, more typically from 0.5 mm to 1.5mm and a length of 10 cm to 240 cm more typically from 75 cm to 150 cm.The catheter extension 307 has a diameter of 0.25 mm to 3 mm moretypically from 0.4 mm to 1 mm and a length of 5 mm to 100 mm moretypically from 5 mm to 40 mm. The balloon pocket 332 has a depth equalto the difference in diameter of the catheter body 306 and the catheterextension 307 and a length of 1 mm to 50 mm more typically from 5 mm to15 mm. The balloon wall thickness and inner diameter are selected,extruded or molded to fit into balloon pocket 332 with minimal balloonextending above of balloon pocket 332.

Referring to FIG. 54B, distal section 330 includes a balloon 338 in aradially constrained configuration held within balloon pocket 332 andhaving an outer diameter approximately equal to the outer diameter ofcatheter body 306.

Referring to FIG. 54C, distal section 330 includes balloon 338 in aradially expanded configuration with channels 314 and one-way valves 316in a closed orientation. Partial occlusion balloon 338 can be any shapeand diameters from 1 mm to 30 mm more typically from 2 mm to 10 mm and alength of 1 mm to 50 mm more typically from 5 mm to 15 mm. Channels 314can be of any shape and configuration and an opening that is calibratedto the desired flow therethrough. In a preferred embodiment, the balloonwill have a diameter of 6 mm and a channel diameter of 0.5 mm to 1.5 mm.Balloon 338, including channels 314 can be formed by molding, extruding,vacuum forming or otherwise shaping a material to include the desirednumber and configuration of channels. Alternately, a standard balloon,including but not limited to, round or oval, can be modified to achieveproximal to distal channels. One method to modify a balloon is byforming longitudinal pleats circumferentially oriented; thereby formingV shaped channels that extend from the proximal end of the balloon tothe distal end of the balloon. Placing a sheath or film over such amodified balloon results in longitudinal channels and a one way valve asdescribed in application 61/917,131.

Referring to FIG. 55A through 55C, a serial construction of the deviceof the present disclosure is illustrated.

Referring to FIG. 55A, a longitudinal view of device construction 350with catheter body 306, distally located catheter extension 307 andproximally located hub 352 comprising guidewire and injection port 354and balloon inflation/deflation port 356.

Referring to FIG. 55B, a longitudinal view of a device construction 350is shown with added nose cone 310 and balloon pocket positioned betweenthe distal end of catheter body 306 and the proximal end of nose cone310.

Referring to FIG. 55C, a longitudinal view of the device 358 of thepresent disclosure is shown with catheter body 306, balloon 340 and hub352. Balloon 340 is shown in a radially expanded configuration withchannels 314 and valves 316 in the open position.

Referring to FIG. 56, an anatomical structure 360 is shown with tumor362, main artery 366, distal main artery 367, side branch arteries 370and 374, tumor capillaries 373, 375, 377 and 379 and blood flowdirection arrows 368, 372, 376 and 378. In the case of a tumor in theright liver lobe, artery 366 is the right hepatic artery and 367 is thedistal right hepatic artery which flow toward the tumor as seen by flowdirection arrow 368 and 378. In this instance, artery 370 is thegastroduodenal artery and artery 374 is a hepatoenteric artery such asthe superduodenal artery, the normal flow of both is away from thehepatic artery, as shown by flow direction arrows 372 and 376, and intoarterial networks which supply both the liver and gastrointestinaltract. Blood from the hepatic artery 366 also flows into the tumorcapillaries 373, 375, 377, and 379. Normal blood flow through the righthepatic artery is in the range of 4 ml/sec.

Referring to FIG. 57A through 57H, a tumor embolization method accordingto current medial practice is shown. At least some of the steps shownare used in current catheter based embolization therapy in tumors of theliver

The first step of the procedure is to advance guidewire 382 from thefemoral artery at the groin, through the iliac artery, aorta, celiacartery, hepatic artery and into the right hepatic artery 366 as inanatomical structure 380 of FIG. 57A. The diameter of guidewire 382 istypically from about 0.25 mm to 1.25 mm more typically from 0.4 mm to 1mm.

In the second step of the procedure, illustrated in FIG. 57B,guide-catheter 392 is advanced over guidewire 382 and along the samearterial path as for guidewire 382. Typically, the guide catheter has anouter diameter of about 1.5 mm to 2.5 mm and has a central lumen thatcan accept a microcatheter with an outer diameter of 0.5 mm to 1.5 mm.The guide catheter is too large to access the vasculature in thevicinity of the tumor and is typically advanced as far along thevascular path toward the tumor as possible. The blood flow follows thesame normal pattern as in FIG. 56 and flows around the sides of guidecatheter 392.

In the third step shown in FIG. 57C, guidewire 382 is optionally removedand replaced with a smaller diameter guidewire 398 that can fit in thecentral lumen of a microcatheter. Guidewire 398 typically has a diameterof 0.2 mm to 0.75 mm, more typically in the range of 0.25 mm to 0.6 mm.

The fourth step of the procedure, microcatheter 3104 is advanced overguidewire 398 to a position beyond the distal end of guide catheter 392and into the vasculature within or in the vicinity of the tumor as shownin anatomical structure 3102 of FIG. 57D. Microcatheter 3104 is advancedas close as is practical to the tumor and, if the anatomy allows, intothe vasculature of the tumor as in superselective embolization.Microcatheter 3104 typically has a diameter of 0.75 mm to 1.5 mm, moretypically at about 1 mm and a total length of 50 cm to 200 cm, moretypically from 75 cm to 150 cm. The central lumen microcatheter 3104 isoptimized to have an inner diameter as large as possible; however it isusually in the range of about 0.5 mm.

In a fifth step, guidewire 398 is removed from microcatheter 3104 asillustrated in anatomical structure 3200 of FIG. 57E. Removal ofguidewire 398 allows the central lumen of microcatheter 3104 to be usedto inject drug and/or embolic materials into the target site within theright hepatic artery and tumor. Blood continues to flow around guidecatheter 392 and microcatheter 3104 and into capillaries 373, 375, 377,and 379 of tumor 362, gastroduodenal branch 370 and hepatoenteric branch374 according to the normal flow pattern shown by arrows 368, 372, 376,and 378.

In a sixth step illustrated in anatomical structure 3208 of FIG. 57F,drug and or embolization agents are injected using a syringe or othermeans from the proximal end of microcatheter 3104 throughguidewire/injection port 354 of hub 52 (FIG. 55), longitudinally throughguidewire injection lumen 334 (FIG. 54), and out the distal end ofcatheter extension 307. In this instance, embolic particles 3210 arecarried by normal blood flow into distal right hepatic artery 3214,tumor capillaries 373, 375, 377 and 379, as illustrated by flow arrow3212, and into hepatoenteric artery 374 in the direction indicated byflow arrow 376. Drug and/or embolization agents that travel throughgastroenteric branch artery 374 or any other arterial branch distal tothe distal tip of microcatheter 3104, by normal forward flow, aredeposited at non-target sites, including parts of the liver andintestine. This antegrade (to the catheter tip) bypass into distalhepatoenteric arteries can cause serious complications including damageor death to sections of the liver or intestine, gastric ulcers or eventhe death of the patient. Further, drug and/or embolic agents thattravel to non-target sites, fail to enter the tumor; this resulting in alower than optimal dose to be delivered to the tumor and a lowerefficacy than desired. However, to avoid the aforementioned seriouscomplications, physicians often under-embolize the tumor vasculature.

Referring to FIG. 57G, as forward flow mediated embolization progresses,the distal ends of capillaries 373, 375, 377 and 379 fill with particles3210 and become embolized. This process dramatically slows the bloodflow moving through the tumor and causes a sharp rise in pressure withinthe tumor vasculature and concomitant retrograde deflection of the highvolume blood flow from the hepatic artery. Further, backpressuredevelops in the distal hepatic artery 3214, resulting in particles toflow in a retrograde direction as in flow direction arrow 3234. This canresult in: (1) increased antegrade bypass into hepatoenteric branch 374,reflux over the catheter and into gastrodudenal artery 370 and (3) asignal to the physician that particle injection should stop, even thoughthe tumor is only partially embolized. In this instance, it is possiblethat larger capillaries become embolized first, due to a larger bloodflow while smaller capillaries remain un-embolized. The rapid rise inpressure is in part caused by distal capillary embolization and in partcaused by the high volume blood flow from the hepatic artery. Given thatembolization is the desired endpoint, it appears that slowing theforward flow of blood from the hepatic artery would allow the tumor toaccept the blood and drug and/or embolic agent flow for a longer periodof time and allow more embolization to occur and an improveddistribution of particles in the tumor vasculature.

Referring to FIG. 57H, injection of drug and/or embolic agents iscomplete, microcatheter 3104 and guide catheter 392 are removed and thefinal embolization distribution in tumor capillaries 373, 375, 377 and379 is shown where, in this example, lager capillary 379 is embolized tothe greatest extent, smaller capillary 377 is embolized to a lesserextent and small capillary 373 remains un-embolized.

Referring to FIG. 58, a method of tumor embolization, according to thedevice of the present disclosure is shown. Steps 1 through step 5, shownin FIGS. 57A through 57E, are the same for both a standard catheter asshown in FIG. 57 and the device of the present disclosure and are notfurther illustrated.

Referring to FIG. 58A, the device of the present disclosure ispositioned in the distal right hepatic artery 3214, with partialocclusion balloon 3256 in its radially expanded configuration comprisingchannels 3258 and 3260, and one-way valves 3262 and 3264 that are in theopen position. FIG. 58A shows two channels, however, one, two, three orany number of channels can be used. With or without valves. The maximumchannel size is limited by balloon diameter, but can be as small as ispractical. Valves 3262 and 3264 can be flap, duck bill, diaphragm, orany type of valve provided that it permits flow only in one direction.Optional pressure sensors 3266, which provides real time pressuremeasurement in the vascular space distal to partial occlusion balloon3256 and pressure sensor 3265 which provides real time pressuremonitoring in the vascular space proximal to the partial occlusionballoon 3256 are shown. Pressure sensor 3266 which measures pressure inthe distal vascular space can be used to signal a procedural endpointbased on a predetermined or non-predetermined pressure reading. Thiswill, for the first time, allow a quantitative and definitive pressuremediated endpoint rather than the present subjective flow mediatedendpoint and will enable the procedure to be reproducible and able to bestandardized allowing center to center and physician to physicianconsistency. This is possible only because the vascular space distal tothe partial occlusion balloon 3256 is isolated from the vascular spaceproximal to partial occlusion balloon 3256, thereby allowing that thearterial pressure in the distal space to be closely related to theintra-tumor arterial blood pressure. Blood flow direction throughhepatic artery 368, distal hepatic artery 3214 and proximal artery 370are normal as seen in flow direction arrows 368, 372 and 378 as is theblood flow in tumor capillaries 373, 375, 377 and 379 and illustrated byflow direction arrows 3212. However, partial occlusion balloon 3256causes a significant reduction in blood flow in distal right hepaticartery 214 and in tumor capillaries 373, 375, 377 and 379. Blood flowcan be regulated by the partial occlusion balloon of the presentdisclosure such that total flow can range from near 100% (unconcludedflow) to near 0% as in full occlusion. Of most interest is partialocclusion that results in 1% to 25% flow as compared to the un-occludedartery. Therefore, channels 3258 and 3220 allow only a fraction ofnormal blood flow to pass distally. Blood pressure distal to partialocclusion balloon 3256 is also dramatically reduced by anywhere fromabout 5 mmHg reduction to 100 mmHg reduction, depending on the nature ofthe occlusion. This pressure drop causes branch artery 374 to reversedirection as seen by flow direction arrow 376 and now flow toward thedistal main artery 3214 and tumor capillaries 373, 374, 377 and 379. Theflow reduction and pressure reduction caused by partial occlusionballoon 256 also reduces the flow and pressure within the tumorcapillaries 373, 374, 377 and 379. This is of significance because itallows more drug/embolization agents to enter the tumor beforebackpressure causes flow stasis and retrograde flow.

Referring now to anatomical structure 3280 of FIG. 58B, injection ofdrug and/or embolic agents is initiated. Blood flow from the proximalmain artery 366 is attenuated as it passes through channels 3258 and3260 and into distal main artery 3214. The anti-cancer agents arecarried by the attenuated forward blood flow through distal main artery3214 and into tumor capillaries 373, 375, 377 and 379. Valves 3262 and3264 are in the open position as pressure in the distal vascular spaceis lower than the blood pressure in the vascular space proximal topartial occlusion balloon 3256. Branch artery 374 continues to flow inthe reverse direction as indicated by flow direction arrow 376 sinceblood pressure in the distal right hepatic artery is lower than that ofthe arterial network connected to the distal end of branch artery 374.In this instance, antegrade drug/embolic agents are prevented fromflowing into branch artery 374 and antegrade bypass and non-targetdelivery does not occur. Optional pressure sensors 3266 and 3265 orpressure measurement through guidewire/injection lumen 334 of catheter 6(FIG. 54A) can be used to monitor real-time pressure.

Referring to FIG. 58C, and looking at anatomical structure 3290, aslower rate of blood flow and lower pressure through distal hepaticartery 3214 allows tumor capillaries 373, 375, 377 and 379 to fill at aslower pace and to a greater distribution than in the current method offull unregulated forward flow. At some point, however, the embolizationof tumor capillaries will cause retrograde deflection of blood andanti-tumor agents and a pressure build up in distal hepatic artery 3214as in FIG. 58D. At this point, the increased pressure in distal righthepatic artery 3214 causes valves 3262 and 3264 to close, preventingretrograde flow and non-target embolization through branch artery 370 orany other arteries proximal to partial occlusion balloon 3256. Thisretrograde deflection and pressure build up will progress at a slowerrate as compared to the current standard method of FIG. 57. The slowerbuildup of pressure and retrograde flow allows a larger time window forthe physician to terminate the procedure. If pressure monitoring isdone, a defined pressure can be used to terminate the procedure. If theback pressure in distal hepatic artery 3214 exceeds about systolicpressure and/or mean arterial pressure, branch artery 374 will againfollow in the normal flow pattern as illustrated in the flow directionarrow 376 of FIG. 56. This situation will allow antegrade drug and/orembolic agents to flow in branch artery 374 and to non-target sites.However, visual observation of contrast movement in branch artery 374 ora defined pressure measurement at or below the flow reversal pressure ofbranch artery 374 can be used as a procedural endpoint signal.

Referring now to anatomical structure 3300 of FIG. 58E, the procedure iscomplete and catheter 3254, of the present disclosure, and guidecatheter 3252 are removed. The distribution and filling of tumorcapillaries 373, 375, 377 and 379, using the device of the presentdisclosure, are improved as compared to the distribution and fillingassociated with the current microcatheter 3104 of FIG. 57H.

In some embodiments, a pressure feedback loop is implemented to controlthe rate of fluid introduction (e.g. the rate of embolic beadinjection). In such embodiments, a blood pressure sensor may be locatedat the distal tip of the catheter to monitor the pressure of thevasculature distal to the occlusion or partial occlusion structure. Insome embodiments, a predetermined pressure set point may be used. Theset point may be an absolute pressure, or a percentage of systolicand/or mean arterial pressure (such as about 100% of systolic and/ormean arterial pressure). Such systems can be programmed to maintain thedistal vasculature at or below the set point by automaticallycontrolling the infusion rate (e.g. the rate or pressure of an injectionpump.) By ensuring that the pressure of the distal vasculature does notexceed systolic and/or mean arterial pressure, retrograde and/or otherundesirable blood flows can be prevented.

In some embodiments, a rate of pressure change can be used instead of orin addition to a preset pressure in the pressure feedback loop. Forexample, if the distal vasculature pressure begins to rise faster than apredetermined rate, the rate of embolic substance injection can beslowed, temporarily stopped, or a procedural endpoint may be signaled.The endpoint signal may be an audible, visual, tactile or other signalto persons involved in the procedure, and/or may be a signal thatautomatically shuts off or changes the state of medical equipment usedin the procedure.

FIGS. 59A-59D show the fabrication steps of the distal end of anocclusion catheter 400 according to aspects of the present disclosure.

FIG. 60 shows the completed distal end 402 of the occlusion catheter 400of FIGS. 59A-59D being introduced into small branches of a vascularsystem 404. The two enlarged contact points 406 and 408 of this designallow the catheter 400 to be navigated into smaller vasculature than canbe navigated by conventional catheter tips.

FIG. 61A shows an entire occlusion catheter constructed according toprinciples of the present disclosure. FIG. 61B shows details ofconstruction features on the distal end 402 of the occlusion catheter400 of FIG. 61A. These details include a catheter extension 410 (whichmay comprise a coaxial inner catheter) extending from the distal end 412of the catheter body 414, which includes a balloon pocket section 416and a distal tip section 418. A nose cone radio-opaque marker 408 islocated at the proximal end of the distal tip section 418, and aradio-opaque marker 406 is located at the distal end of the distal tipsection 418. As previously mentioned, both markers 406 and 408 haveenlarged diameters as compared with the diameter of the adjacent distaltip section 418.

Referring now to FIG. 62, an axial cross-section of an alternativecatheter balloon design is shown. In this design, a single balloon 560is concentrically aligned over inner catheter 562. During manufacture,balloon 560 is longitudinally bonded to inner catheter 562 in twolocations 564 and 566, circumferentially spaced 180 degrees apart. Thisarrangement provides two generally V-shaped channels 568 and 570 whenballoon 560 is inflated, as shown. These longitudinal V-shaped channelskeep balloon 560 from fully occluding a blood vessel by allowing aportion of the normal blood flow to bypass the balloon through thechannels. By specifying and controlling the dimensions of thisconstruction, predetermined bypass flow rates may be obtained.

The longitudinal bonds 564 and 566 may be formed by ultrasonic welding,heat staking, adhesive, fasteners, or other suitable arrangements. Innercatheter 562 many include flat portions or grooves where the bonds arelocated, as shown, or may have an entirely round circumference. In otherembodiments (not shown), a single channel or more than two channels maybe formed. The channel(s) may run the entire length of the balloon orless than the entire length. In some embodiments the balloon segmentswhen inflated may be more rounded than those shown in FIG. 62.

Referring now to FIGS. 63 and 64, a catheter balloon having spiralchannels is shown. FIG. 63 shows one embodiment in a deflatedconfiguration while FIG. 64 shows the balloon in an inflatedconfiguration. The balloon can be slender and elongated, and wrappedaround the inner catheter in a spiral fashion leaving a spiral channelformed between windings. In this arrangement, the balloon can beinflated from its proximal or distal end. Alternatively, a largerballoon can be placed coaxially over the inner catheter and secured inplace by a spiral wound wire. When the balloon is inflated, only theportions between the wire winding will inflate, leaving a spiral channelhaving a wire running along its inner diameter. In some embodiments, thecoaxial balloon can be bonded to the inner catheter, as previouslydescribed but in a spiral rather than a straight fashion. Two or morewires or bonds can be placed in parallel, forming two or more separatebut interlaced spiral channels. With any of these configurations, thespiral channels can be sized to provide the desired range of bypassflows across the occlusion balloon.

Referring now to FIGS. 65-73, additional embodiments are shown anddescribed, as well as animal testing results and refined understandingsof flow models for previously described embodiments. In conjunction withthe following descriptions the following definitions are used:

A “Drug” includes, but is not limited to, embolic agents, therapeuticagents, anticancer agents, fillers, glue, foam, ablative agents,sclerotherapy agents, contrast agents, nutrients, and any fluid ormaterial that can be delivered through the lumen of a catheter.

“Mean arterial pressure” is the mean blood pressure at a particularpoint or points in the arterial vessel system during a particular timeperiod as the blood pressure varies between the systolic pressure andthe diastolic pressure with each pulse.

“Normal mean arterial pressure” is the mean arterial pressure at aparticular point or points in the arterial vessel system when notemporary occlusions are in place.

A “Target” is a tissue, organ, defined space within a tissue, part of anorgan, tumor, or any other anatomical structure, in whole or in part,such as primary and metastatic tumors, prostate, uterus, pancreas,spleen, bladder, stomach, kidney, liver, gallbladder, thyroid, eye andbone and any other tissue or organ system in the human body.

A “Supply Artery” is one that delivers blood to the target and is influid communication with one or more collateral vessels, arteries,arterioles, capillaries, and/or anastomotic vessels.

A “Collateral” includes, but is not limited to, an artery, arteriole orcapillary that branches from or anastomoses to and is in fluidcommunication, either directly or through interstitial flow, with thesupply artery. Collateral Arteries supply normal tissues.

An “Anatomical Zone” is an area surrounding that portion of the supplyartery that is distal to an occlusion. In some embodiments of thepresent disclosure, the supply artery distal to an occlusion has apressure substantially lower than normal mean arterial pressure.

A “Normal Gradient” comprises arterial pressures that define normal flowcirculation in the human body.

A “Redistribution Gradient” comprises arterial pressures that resultfrom an occlusion in a Supply Artery which causes flow to redistributeand move toward a low pressure, into a target, and away from healthytissues.

Blood flow follows pressure gradients. Normal (un-occluded) bloodpressure in the supply artery is higher than that of the collaterals andthe collaterals may have a pressure higher than that of the target.

In general, the normal pressure gradient (Normal Gradient) is asfollows: Supply Artery>Collaterals>Target. The supply artery may have apressure at or near the mean arterial pressure of the heart which ispatient dependent, however, typically has a pressure in the range of 60mmHg to 110 mmHg. According to aspects of the disclosure, the area ofthe supply artery distal to an occlusion of the supply artery istypically 10% to 60% below the normal mean arterial pressure at thatarea.

Under normal physiological conditions and due to the aforementionednormal pressure gradient, the supply artery flows into both thecollateral arteries and into the target and is associated withinterstitial flow in the surrounding Anatomical Zone. Thereby blood flowin a collateral vessel typically travels away from the supply artery andinto healthy tissues.

Collaterals are arteries that branch from the supply artery and areconnected to capillary beds that have more than one blood supply andinherently have pressure that may be attenuated below the mean arterialpressure of the supply arteries. When a temporary occlusion isintroduced in the supply artery according to the present disclosure, anew pressure gradient (Redistribution Gradient) and related flowredistribution results.

A temporary occlusion is created using a balloon catheter or any otherocclusive device or a partially occlusive device. In some embodiments, apartial occlusion device is configured to allow a bypass flow volume inthe order of 5% to 25%. To ensure a large pressure gradient, in someembodiments the bypass flow volume is between 5% and 10%, inclusive. Theocclusion device can be positioned on a catheter, needle, cannula or thelike and can be delivered percutaneously, intravenously or surgically.

As a result of the occlusion, the area distal to the occlusion of thesupply artery has a lower pressure than the Normal Mean ArterialPressure of the Anatomical Zone. The occlusion causes the flow in thesupply artery to stop, or be substantially reduced, and new pressuregradient is Collaterals>Supply Artery>Target. In this instance, flowredistribution moves blood from the collaterals and into the targetthrough the supply artery (Redistribution Gradient).

Targets that have terminal capillary beds will continue to accept flowfrom collateral arteries and the Anatomical Zone, whereby inward bloodflow exits through the target into veins that have a very low pressureat about 10 mmHg. Targets can have sump like properties that “drain” theinflow of blood that moves toward the low pressure zone. Due to theterminal capillary beds, targets can have a lower pressure thancollateral arteries and associated capillaries.

In this instance, mass flow of capillaries, arterioles and arteries ofthe Anatomical Zone will be directed toward the low pressure zone of theTarget. This includes capillaries distal to the occlusion and in thevicinity of the Target. When drug is injected through the catheter,redistributed blood flow will carry the drug exclusively into theTarget, and flow of the drug through the collaterals and into healthytissue will not occur. During the time that the occlusion of the supplyartery is in place, the area surrounding the low pressure anatomicalzone will flush into the low pressure zone through the capillary bedsthat are normally fed by both the Supply Artery and other sourcearteries. To create this reverse flow from the capillary beds, a lowpressure anatomical zone is maintained by the temporary occlusion.

In the case of tumor embolization, tumors have terminal capillaries andthe aforementioned method will create flow into the tumor. In the caseof prostate artery embolization (PAE), the prostate has terminalcapillaries and the aforementioned method will create redistributed flowinto the prostate. By performing the method on both of the main arteriesfeeding the prostate, ischemia in the entire prostate can be achieved,shrinking it by at least 10%.

In the case of embolization therapy, such as in tumor embolization,pressure measured in the vessels distal to the occlusion can be used toquantitatively detect embolization endpoint as previously described,since pressure will rise as embolization of the target progresses. Anautomated injection system can control embolization agent injectionpressure to maintain a favorable pressure gradient.

Referring now to FIGS. 65 and 66, a representative arterial systemlocated adjacent to target tissue is shown. FIG. 65 depicts therepresentative arterial system before occlusion, and FIG. 66 depicts thesame arterial system after a temporary occlusion is introduced. Bloodflow direction is shown by arrows 503. Before occlusion (FIG. 65), bloodflows from supply artery 501 into target artery 525 feeding targettissue 527. Eventually blood makes its way into the terminal capillariesof target 527. The terminal capillaries include the arterial side 531,the venous side 533, and the arterial venous interface 535 therebetween.

In addition to feeding target 527, supply artery 501 feeds a firstcapillary bed 509 through a first collateral artery 505, and a secondcapillary bed 511 through a second collateral artery 507. Capillary beds509 and 511 each contain hundreds of capillaries. Supply artery 501typically will feed more than two capillary beds but only two are shownfor ease of understanding. Reference numerals 517 and 519 depict theposition of healthy tissue fed by first capillary bed 509, and referencenumerals 521 and 523 depict the position of healthy tissue fed by secondcapillary bed 511. In addition to being fed by first collateral artery505, first capillary bed 509 is also fed by a secondary arterial supply513. Similarly, in addition to being fed by second collateral artery507, second capillary bed 511 is also fed by a secondary arterial supply515. Capillary beds 509 and 511 may each be fed by more than twoarteries but only two are shown for ease of understanding.

Under a normal pressure gradient, the mean arterial pressure at eachpoint along a blood flow path typically goes down as blood flows fromsupply artery 501, through collateral artery 505, 507, and target artery525, through arterial side capillaries 531 and into venous sidecapillaries 533. This reducing pressure is what causes the blood tocontinue flowing through the arterial system. In some patients, atypical pressure gradient would include a mean arterial blood pressureof 90 mm Hg in supply artery 501, a pressure of 60 mm Hg in collateraland target arteries 505, 507 and 525, and a pressure of 20 mm Hg interminal capillaries 529. Typical flow rates could be about 3 to 5ml/sec in the artery that feeds supply artery 501, 2 to 3 ml/sec insupply artery 501, and 0.5 to 1.0 ml/sec in collateral and targetarteries 505, 507 and 525.

As shown in FIG. 66, a balloon catheter 537 may be introduced into thearterial system of FIG. 65, such as through a femoral or radial artery.Once in place, balloon 539 may be inflated to partially or fully occludea proximal portion of supply artery 501. The target 527 continues todraw blood into it, acting as a sump. According to some aspects of thepresent disclosure, the mean arterial blood pressure in supply artery501 drops 10 to 60% below its normal, un-occluded state in the vascularspace distal to the occlusion. In some embodiments, the drop in pressureis between 5 and 90% below normal. In some embodiments, the drop inpressure is between 20 and 40% below normal. This drop in pressurecauses a redistribution pressure gradient and redistributed blood flow,which includes blood flowing in an opposite direction in some vesselsdistal to the occlusion. In particular, blood flows in a reversedirection in collateral arteries 505 and 507, and in the distal end ofsupply artery 501, as shown by flow direction arrows 503. Instead ofblood flowing from supply artery 501 to capillary beds 509 and 511,blood instead flows in a reverse direction from capillary beds 509 and511, through supply artery 501 and into target 527. During thisredistributed flow, capillary beds 509 and 511 are not adverselyaffected since they continue to be fed by at least secondary arterialsupplies 513 and 515, respectively. This redistributed flow ensures thatembolization agents and/or other drugs emanating from balloon catheter537 are carried toward target 527 and do not migrate into healthy tissuesuch as 517, 519, 521 and 523. Partial blood flow past occlusion balloon539 may be used to carry drugs from a region of supply artery 501 justdistal to balloon 539 towards and into target 527.

During the redistributed blood flow described above, and as a result ofa lower pressure in the Anatomical Zone, it is believed that there is ageneral flushing of fluids toward the low pressure zone which protectshealthy tissue from non-target drug flow. Initial testing indicates thatlower pressure gradients and lower blood flows result in better tumorfilling with embolization agents.

Referring now to FIGS. 67 and 68, a modified method will be describedthat is similar to the method previously described in relation to FIGS.65 and 66. In FIGS. 67 and 68 the catheter is moved up into targetartery 651, which is analogous to target artery 525 shown in FIGS. 65and 66. FIG. 67 shows the target anatomy un-occluded while FIG. 68 showsan occlusion balloon 673 in place and inflated, causing a redistributionpressure gradient.

In this instance, target 663 can be an organ, tissue, tumor or any otheranatomical structure that has a terminal capillary bed (i.e. emptiesdirectly into the venous system) such as a prostate, pancreas, liver,kidney or other organ, in whole or in part. The arteries, arterioles andcapillaries of the target can have collaterals which feed networks thatcan be within another organ or tissue and have an arterial supply 675.The target capillary bed 665 (having arterial side 667 and venous side669) may have similar pressures to the capillary beds 659 and 661 whichcan be within an organ or tissue. Thereby flow may travel in eitherdirection as seen by arrow 653 of FIG. 67. In FIG. 68, the occlusionballoon 673 of catheter 671 blocks the flow of target artery 651 andcauses a pressure drop in the target 663. When the pressure of target663 drops, collateral arteries 655 and 657 flow only into target 663 asindicated by arrow 653 of FIG. 68. In this manner, drug delivery into ananatomical structure such as target 663 can be enhanced by occluding theartery or arteries that feed the target. The pressure in an anatomicalstructure can be lowered and blood and fluid flow will be directedexclusively toward the target anatomical structure.

Referring now to FIG. 69, a chart is provided showing pressure vs. timefor an exemplary low pressure embolization method according to aspectsof the present disclosure compared with a standard embolizationprocedure. The low pressure method is depicted by line 550 and thestandard method is depicted by line 552. For both methods the horizontalaxis represents time (in minutes) elapsed since the pressuremeasurements started and the vertical axis represents the mean arterialpressure (in mm Hg) in the vascular space distal to the tip of theembolization catheter. At times 1 minute to 4 minutes, the line of thestandard method (552) and the low pressure method (550) overlap at thenormal mean arterial pressure which is, in this case 120 mmHg. In thestandard procedure 552, release of the embolization agent begins around4 minutes. Because an occlusion device is not used, as the embolizationagent is injected and the embolization progresses, the pressureincreases above the mean arterial pressure to 150 mmHg at minute 7. Oncethe injection stops at 7 minutes, the pressure will no longer increaseand over a time may return to the mean arterial pressure at minute 11 asthe collateral arteries are able to accept the normal blood flow. Incontrast to the standard embolization procedure, at minute 4 in theexemplary low pressure procedure 550 an occlusion structure, such as aballoon, is expanded into an occlusion configuration in the supplyartery, as previously described. Since blood flow into the supply arteryis partially or fully occluded by the structure, the pressure drops(sometimes to zero, or close thereto) and stabilizes at 80 mmHg, whichis 40 mmHg below normal mean arterial pressure. The pressure drop isstable until embolization injection starts at minute 8. In this instancethe pressure drops from 120 to 80 mm Hg, or about 33%. At minute 8injection of embolization agent is begun through the balloon catheterinto the supply artery. The injection is done at a low pressure and at aslow flow rate to ensure that the redistribution pressure gradient ismaintained. In some embodiments, the embolization flow rate ismaintained between 0.25 to 6 ml/minute and/or a flow rate that keeps thepressure rising slowly, such as in the example shown in FIG. 69. Betweenminutes 8 and 16, the tumor is progressively filling with moreembolization agent and therefore accepting less blood from the supplyartery, thereby allowing the pressure to rise. In this example, thetumor is embolized around minute 16, causing the pressure to level offat 100 mm Hg. The pressure leveling off or reaching a predeterminedpoint may be used to signal the endpoint of the procedure. By using thislow pressure and slow flow approach, the tumor can be filled morecompletely than with the standard procedure, and embolization agent canbe kept away from healthy tissue adjacent the tumor. In initial testing,the methods disclosed herein allow a tumor to fill with 2.4 times asmany microbeads of embolization agent compared with standard procedures.Initial testing indicates that the mean arterial pressure just distal ofthe occlusion should be kept below the starting pressure by at least 10to 30% of the difference between the un-occluded starting pressure andthe stabilized occluded pressure to maintain the Redistribution Gradientand optimal tumor filling. In the example of FIG. 69, the startingpressure is 120 mmHg and the stabilized occluded pressure is 80 mmHg,yielding a difference of 40 mmHg. 10 to 30% of this difference is 4 to12 mmHg, so the pressure during tumor filling should be kept below 116to 108 mmHg for optimal filling. The lowered pressure may be maintainedby limiting the pressure and/or flow rate of the embolization agent. Itshould be noted that this pressure ceiling range also applies todispensing other drugs in other procedures targeting certain targettissue and is not limited to dispensing embolization agent.

The following is a summary of an animal study conducted during thedevelopment of the methods and devices disclosed herein.

Animal Study Approach

FIGS. 70-72 show the in-vivo tumor flow model developed in Phase 1B ofthe testing. A capillary is inserted into a hepatic artery that has atleast one or several branch hepatoenteric arteries, arterioles,anastomotic vessels and/or capillaries that normally flow away from thehepatic artery. The proximal end of the capillary is open producing alow pressure “pseudo-tumor”. When particles are injected as in FIGS.70-72, the blood and particles can be collected. FIG. 70 alsoillustrates a normal blood flow pattern in a patient with a tumor asindicated by arrows. Blood will flow away from higher pressure andtoward lower pressure. Systolic pressure is higher than that of brancharteries, capillaries, and tumor, thereby blood flows both into thebranch arteries toward healthy tissue and into the tumor.

Current Method:

Presently, standard delivery catheters are used for tumor embolization.Typically, the catheter tip is positioned in an artery proximal to boththe tumor and one or several branch arteries and capillaries that flowaway from the tumor as shown in FIG. 71. When embolic agents areinjected, the flow pattern remains normal as in FIGS. 70 and 71 suchthat particles are distributed between the tumor feeder artery(s) andbranch arteries that feed healthy tissues and organs. In addition, theright hepatic artery of FIG. 71 is flowing at about 2-4 ml/sec. Theextensive capillary beds of the tumor can normally accept this high rateof flow. However, at the onset of embolization, larger tumor capillariesbecome blocked, high intra-tumor pressure causes tumor flow to beprogressively and sharply reduced; this limiting the extent ofembolization (analogous to filling a tea cup with a fire hose). Forthese reasons, efficacy and reproducibility of present embolizationtherapy are far from optimal.

Occlusive Method:

According to the method developed in Phase I and illustrated in FIG. 72,an occlusion balloon is expanded in the right hepatic artery totemporarily occlude flow. Immediately following the balloon inflation,the blood pressure distal to the balloon drops significantly and in theorder of 10-50 mmHg. When the pressure is reduced distal to theocclusion, branch arteries and capillaries reverse flow, following thepressure gradient as in FIG. 72. Because the tumor has the lowestpressure, all blood flow is directed into the tumor whereby non-targetflow into branch arteries no longer can occur. The tumor has extensiveterminal capillary beds that exit into low pressure veins, therebycreating a sump-like effect that accepts the flow from the reversed sidebranches which have a much slower flow rate as compared to theunobstructed right hepatic artery. The net result is that all embolicagents are directed into the tumor at a reduced flow rate, whereby thetumor filling is improved while the surrounding non-cancerous tissue isprotected.

Animal Study Protocol (Used for Phase IB and Phase II)

Using contrast injected through a guide catheter placed into the celiacartery and with fluoroscopic imaging, select locations for placement ofthe Inventive Occlusion Balloon Catheter and the AccuStick (BostonScientific) Catheter as in FIG. 70.

Under fluoroscopic guidance, advance the Inventive Occlusion BalloonCatheter within hepatic artery to a position that is 2 to 6 cm proximalto the location selected for the AccuStick, making sure that there arebranch arteries between the distal tip of the Inventive Catheter and theAccuStick.

Perform a laparotomy and use visual examination (with ultrasoundassist), of the liver and associated arteries and identify the tip ofthe Inventive Catheter in the hepatic artery and the distal arteryselected for insertion of the AccuStick.

Make a small incision in the arterial wall and insert the AccuStick intothe artery. Secure with suture.

Connect the proximal end of the AccuStick to ⅛″ tubing, including anadjustable stopcock, and extend the tubing to a blood collection vesselas in FIGS. 70-72.

Using a Pendotech in-line pressure transducer connected to the proximalinjection lumen of the Inventive Occlusion Balloon Catheter (FIG. 76)measure blood pressure through the catheter with the balloon in theunexpanded configuration (P0, Standard Pressure).

Inflate the occlusion balloon and measure the pressure (P1) at the tipof the catheter, noting flow of branch arteries via contrast injection.

While measuring blood pressure, begin to open stopcock of AccuStick (or19 gauge needle) until the pressure reading at the tip of the catheteris 10-30 mmHg lower than Standard Pressure while collecting blood in aflask as seen in FIGS. 70-72, noting flow of branch arteries viacontrast injection. Measure blood pressure (P2).

Inject microparticles through the Inventive Occlusion Balloon Catheterwhile collecting blood.

Following the completion of microparticle injection, allow the blood toflow for an additional several minutes, and then close the stopcock.

Measure blood pressure (P3).

Repeat the microparticle injection 2 more times with the balloon in itsexpanded configuration, collecting blood in a new vessel for eachreplicate.

Repeat the microparticle injection 3 times with the balloon in itsunexpanded configuration, collecting the blood in a new centrifuge tubeeach time.

Repeat steps 1 through 10 on a second pig.

Isolate the microparticles using filtration and suspend in 250 μL ofsaline. Determine yield by weight (Phase 1B) or particle count.

Compare results from inflated balloon and uninflated balloon. Improvedparticle recovery from the balloon up condition as compared to theballoon down condition is considered to be a validation of the theory.

Discussion

As in the Phase IB Project Description, 2 animals will be used to testthe in-vivo tumor model design that is illustrated in FIGS. 70-72.

The Phase 1B pig study has been completed and the results shown in FIGS.A, B and C (not adequately reproducible for patent application) whichare contrast enhanced fluorographic images taken during the animalprocedure.

FIG. A (not in patent application) shows an angiogram of the vascularstructure in the pig's liver showing artery 2 which is the right hepaticartery, artery 1, a branch off the right hepatic and arteries 3-5 whichare other hepatic and hepatoenteric arteries. The marker bands of theInventive Catheter are seen in the common hepatic artery. In this figurethe, contrast was injected through the guide catheter with its [balloon]positioned proximal to the Inventive Catheter tip. The tip of the guidecatheter is positioned in the celiac artery as it exits the aorta. Thispositioning is the reason that the entire vascular tree is visualized.Since the guide catheter used in this study had a 5 Fr inner diameter,contrast was injected at a high flow and the vascular tree is relativelydark.

Also noted in FIG. B (not shown) is the placement site of the“pseudo-tumor” catheter in distal artery 3. The blood from the catheterplaced in artery 3 was collected in a test tube as shown.

FIG. B (not shown) is a fluorographic image of the Inventive Deviceplaced in the common hepatic artery as evidenced by the marker bands. Inthis instance, the Inventive Balloon was down which is equivalent to astandard catheter that is currently used for tumor embolization. Thistime, contrast was injected through the Inventive Catheter and theangiogram (lighter because the slower contrast flow rate through amicrocatheter) shows the same arterial tree as in FIG. A (not shown)with arteries 1, 2, 3, 5, & 6 visible. Artery 4 could not be seenbecause the contrast concentration was insufficient to visualize thisartery. Figure C (not shown) illustrates what happens when the balloonis inflated. In this case only the tumor feeder artery 3 is visible.When contrast was injected using a power injector at about 3 ml/sec,contrast was forced up branch arteries 1, 2, 4 & 5, however once thecontrast injection stopped, contrast in the branch arteries flushed backinto the tumor feeder artery 3, this demonstrating flow reversal ofthese non-tumor arteries.

Particle Injection:

Embolic particles (100-300μ, Merit Medical) were injected under theconditions seen in both FIG. B (not shown—standard condition) and FIG. C(not shown—inventive condition).

According to the method as stated above, blood pressure would dropimmediately following balloon occlusion and stabilize in the vascularcompartment distal to the occlusion. In fact, it is this pressurereduction that causes flow reversal of branch arteries and blood flowdirected exclusively into the tumor. Pressure was measured through thecatheter using an in-line pressure transducer located at the proximalend of the catheter. According to the Phase 1 theory, the pressure inthe vascular compartment distal to the balloon occlusion wouldimmediately drop to a pressure lower than systolic, but not to zero. Thepressure is non-zero because of the flow reversal of branch arteries andcapillaries which are part of arterial networks. These networksinherently have a pressure due to the multiple sources that are feedingthe network. In this instance, the blood pressure in the networks isattenuated given the multitude of vessels in the network. As a point ofinterest, when the Inventive Catheter Balloon is up, the blood pressurethat is measured is that of the arterial networks and inward flow ofother vessels. In one experiment, the initial blood pressure is about 67mmHg which rapidly drops when the balloon is inflated to below 35 mmHg,then stabilizes at about 48 mmHg, a pressure drop of 19 mmHg. Duringparticle injection, the pressure reading is not attainable using thisin-line sensor. Following injection, the pressure returns to aboutsystolic. This data again meets the Phase 1 expectations.

The occlusion microcatheter of Phase 1 has been successfully developedand tested and is, at this point, clinically capable. In addition, itappears that the new animal study design is feasible and has alreadyprovided quantitative results that are consistent with the Phase 1theory.

Phase IB Animal Study (for Set Up)

This study was used to test and optimize the proposed protocol prior touse in the final Phase I animal study. This study included 2 pigs andfollowed the protocol outlined above. For each animal there are 3balloon up replicates and 3 balloon down replicates or 6 data points peranimal. Following collection of the beads, the following table shows thedata points from each animal averaged in the balloon up and balloon downcases:

Fold increase in Animal # Balloon Down Balloon Up Delta (g) bead capture1 0.45 g 0.92 g 0.47 g 2.04 2 0.15 g 0.22 g 0.07 g 1.46

Discussion:

The animal study of Phase IB showed a significant increase in particlescollected when the balloon was up. This is consistent with the expectedresults and the theory set forth in the present project. However, as inFIGS. B and C (not shown), the difference between the balloon up andballoon down conditions appears to be visually greater than 2× and itwas noted that weight differences are difficult to measure accuratelysince the cell strainer has a mass many times that of the beads. Thetotal mass of beads that were injected was 1.0 g. It is noted that thetotal recovery in animal #1 is reasonable while that of animal #2 islow. It is believed that the tumor catheter leaked at the entry to thetumor artery due to an incomplete seal.

Conclusions:

The animal protocol as in the Phase IB is shown to be quantitative andfar better than that initially described. As such this new protocol willbe used for the final Phase 1 study. The following improvements will bemade:

Use particle count as a means to measure each condition rather than mass

Suture the tumor catheter in place and make sure there are no leaksthroughout the study

Phase 1 Animal Study (Aim #3 of the Phase I Project Description)

The Animal Study Protocol of Phase IB, will be used.

Materials and Methods

Animals used: American Yorkshire Pigs, 75 Kg+15 Kg

Microbeads: CeloNova Embozene® Microsphere

400 μm—blue; REF 14020-S1

250 μm—yellow; REF 12020-S1

2 ml syringe reconstituted to 8 ml total with 100% contrast

Excess fluid removed after beads settle in syringe

Contrast (100%) added to help maintain bead constitution in fluid

2 ml beads+6 ml contrast=8 ml total volume

Split to (2) 1 ml samples of 4 ml each

Injected via stopcock using 1 ml injection syringe

Study Algorithm

24 data sets (12 pairs) Analyzed

First Test Date:

Pig 1: data rejected, abnormal vascular anatomy

Pig 2: 8 data sets (4 pairs) 3 pair analyzed

-   -   250 μm & 400 μm balloon up & down (×2)        -   2nd 250 μm data set not analyzed—clot blocked blood flow        -   proximal to catheter

Pig 3: 6 data sets (3 pair) 3 pair analyzed

-   -   250 μm balloon up & down (×2)    -   400 μm balloon up & down (×2)

Second Test Date:

-   -   Pig 1: 6 data sets (3 pair) 1 pair analyzed        -   250 μm balloon up & down (×2)            -   1st 250 μm data set not analyzed—placement too close to                tumor model; no branch arteries between catheters        -   400 μm balloon up & down (×1)            -   Note: 400 μm would not reconstitute after                collection—data not analyzed    -   Pig 2: 6 data sets (3 pair) 3 pair analyzed        -   250 μm balloon up & down (×2)        -   400 μm balloon up & down (×1)    -   Pig 3: 4 data sets (2 pair) 2 pair analyzed        -   Anatomy limited testing to 1 catheter location        -   250 μm balloon up & down (×1)    -   400 μm balloon up & down (×1)        Bead Count Methodology

Beads collected in cell filter

-   -   Falcon, 70 μm filter    -   Cleaned with water

Beads mixed with 25 ml water

Magnetic mixer homogenizes beads

250 μm analysis:

-   -   100 μl pipette placed on slide 400 μm analysis:    -   250 μl pipette placed on slide

3 samples taken for each collection

-   -   Min/Mid/Max    -   Counted under microscope

Extrapolate to full 25 ml mix

-   -   Ex: bead count/pipette volume*25 ml solution=beads collected        Discussion

The in-vivo model described herein is intended to emulate anatomicalstructure and flow dynamic properties associated with a tumor in thehuman liver. The low pressure pseudo-tumor described herein ischaracteristic of a tumor which functionally behaves like a sump sincethe vast capillary bed within a tumor empties directly into veins thathave near zero pressure. Examination of contrast flow with the balloondown (straight tip catheter) and the balloon up (occlusive condition)demonstrate flow redistribution in favor of the pseudo-tumor when theballoon is occlusive. It is therefore not surprising that injection withthe balloon up always resulted in a much higher (average 2.4 times)amount of beads collected. Furthermore, it is evident that when theballoon is down, fewer beads are collected and the balance of the beadsare randomly distributed among the branch arteries and healthy tissues.The bead collection results of this study are summarized in the table ofFIG. 73.

It is noted that Bead recovery may be impacted by multiple sequentialbead injections in the same animal due to embolization of brancharteries. We believe that this favors the balloon down condition sincenon-target flow into occluded arteries cannot occur. In order tominimize this effect, the first injection was done at a location closestto the low pressure zone and the second injection furthest from the lowpressure zone. It is likewise noted that the pseudo-tumor is neverembolized and remains as a “sump”. This too will impact the relativebead collection between the balloon up and balloon down conditions.Further study is needed to elucidate a broader understanding ofembolization at a low pressure.

Conclusions of Animal Study

The in-vivo flow simulation of a liver tumor shows that balloonocclusion consistently results in a sizable increase in the quantity ofembolic particles delivered to a “pseudo tumor”. The explanation forthis phenomenon is clearly a function of pressure gradients that resultfrom blockage of the high pressure supply artery and redistribution ofblood flow in favor of the tumor. Normal unoccluded flow is driven bythe supply hepatic artery that has the highest pressure and flow rate.Thereby the normal flow is characterized by the following pressuregradient: hepatic artery pressure is greater than branch arterialnetwork pressure which is greater than tumor pressure. In contrast, whenthe hepatic artery flow is stopped, the AP between the branch arterialnetworks and the tumor creates a flow from the capillary networks intothe tumor. It follows that balloon occlusion produces a favorable flowpattern that directs injected agents exclusively into the tumor and anabsence of embolic agent flow toward healthy tissues. It is alsospeculated that occlusion of the high flow supply artery and subsequentredirection of branch arteries results in a substantial reduction in therate of flow into the tumor, this allowing an improvement in tumorfilling. We conclude that the mechanism behind the observed improvementin tumor filling is directly related to a low distal pressure thatresults from balloon occlusion. Low Pressure Embolization will enable anew era of tumor embolization with improvements in both safety andefficacy. The method should also make tumor embolization to be lesstechnique dependent and provide improved center to centerreproducibility.

It is important to note that in some embodiments of the presentdisclosure the devices regulate flow and pressure in the arterial spacedistal to the partial occlusion balloon, significantly reducing flowrate and pressure in tumor capillaries and cause flow reversal of distalbranch arteries. These devices and methods thereby enable substantialelimination of retrograde and antegrade flow to non-target sites and amore complete filling of the tumor vasculature with drug and or embolicagents and should improve efficacy and reduce complications overstandard devices and methods.

What is claimed is:
 1. A method of transarterial embolization agentdelivery at a low pressure, the method comprising: advancing a deliverydevice with an occlusion structure in a retracted non-occlusiveconfiguration, through a supply artery having a plurality of collateralvessels that branch therefrom and being in fluid communication with atarget anatomical structure, to a vascular position in the supply arterythat is in the vicinity of the target anatomical structure, the targetstructure having terminal capillary beds; expanding the occlusionstructure from the retracted non-occlusive configuration to an expandedocclusive configuration; lowering a mean arterial pressure in a vascularspace distal to the expanded occlusion structure; redirecting fluid flowfrom the collateral vessels toward the lowered pressure vascular spaceand into the target anatomical structure; injecting an embolizationagent through the delivery device and into the lowered pressure vascularspace; and delivering the embolization agent from the lowered pressurevascular space into the target anatomical structure, wherein the meanarterial pressure of the lowered pressure vascular space is kept belowan un-occluded starting pressure by at least 10% of the differencebetween the un-occluded starting pressure and a stabilized occludedpressure during the injecting step.
 2. A method according to claim 1,wherein the mean arterial pressure in the lowered pressure vascularspace is lowered during the lowering step to between 10% and 60% of anormal mean arterial pressure.
 3. A method according to claim 1, whereinthe lowering step comprises measuring a pressure in the vascular spaceafter expanding the occlusion structure.
 4. A method according to claim3, wherein the lowering step further comprises ensuring the measuredpressure is within a predetermined range before proceeding with theinjecting step.
 5. A method according to claim 1, wherein the loweringstep comprises waiting a predetermined period of time before proceedingwith the injecting step to ensure that a sufficient pressure drop hasoccurred.
 6. A method according to claim 1, wherein the fluid ispredominantly blood.
 7. A method according to claim 1, wherein the fluidis predominantly interstitial fluid.
 8. A method according to claim 1,wherein the embolization agent is injected with a flow rate in the rangeof 0.25 to 10 ml/minute.
 9. A method according to claim 1, wherein thedelivery device comprises a catheter.
 10. A method according to claim 1,wherein the delivery device comprises a needle.
 11. A method accordingto claim 1, wherein the delivery device comprises a cannula.
 12. Amethod according to claim 1, wherein the occlusion structure allows afluid flow of 5 to 25% of normal to bypass the occlusion structure afterit has been expanded into the occlusive configuration.
 13. A methodaccording to claim 1, wherein the occlusion structure creates asubstantially full occlusion having less than 2% bypass blood flow. 14.A method according to claim 1, wherein the occlusion structure comprisesa balloon.
 15. A method according to claim 14, wherein the balloon isprovided with a generally v-shaped channel extending along a least aportion of its length, thereby providing a fluid bypass channel when theballoon is inflated.
 16. A method according to claim 14, wherein theballoon is provided with a spiral channel extending from a proximal endof the balloon to a distal end, thereby providing a fluid bypass channelwhen the balloon is inflated.
 17. A method according to claim 1, whereinthe delivery device is provided with a pressure transducer locateddistal to the occlusion structure and configured to sense fluid pressurewhen located in the supply artery.
 18. A method according to claim 1,wherein the target anatomical structure is a tumor.
 19. A methodaccording to claim 1, wherein the target anatomical structure is aprostate.
 20. A method according to claim 1, wherein the targetanatomical structure is a uterus.
 21. A method of transarterialembolization agent delivery at a low pressure, the method comprising:advancing a delivery device with an occlusion structure in a retractednon-occlusive configuration, through a supply artery having a pluralityof collateral vessels that branch therefrom and being in fluidcommunication with a target anatomical structure, to a vascular positionin the supply artery that is in the vicinity of the target anatomicalstructure, the target structure having terminal capillary beds;expanding the occlusion structure from the retracted non-occlusiveconfiguration to an expanded occlusive configuration; lowering a meanarterial pressure in a vascular space distal to the expanded occlusionstructure; redirecting fluid flow from the collateral vessels toward thelowered pressure vascular space and into the target anatomicalstructure; injecting an embolization agent through the delivery deviceand into the lowered pressure vascular space; and delivering theembolization agent from the lowered pressure vascular space into thetarget anatomical structure, wherein the mean arterial pressure of thelowered pressure vascular space is kept below an un-occluded startingpressure by at least 30% of the difference between the un-occludedstarting pressure and a stabilized occluded pressure during theinjecting step.